DEPOMED, INC. v. ACTAVIS ELIZABETH LLC et al
Filing
383
REDACTED OPINION re 375 Opinion. Signed by Judge Joel A. Pisano on 8/18/2014. (eaj)
UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF NEW JERSEY
____________________________________
:
DEPOMED, INC,
:
:
Plaintiff(s),
:
:
v.
:
:
:
ACTAVIS ELIZABETH LLC, et al.
:
:
Defendant(s).
:
____________________________________:
***REDACTED***
Civil Action No. 12-1358 (JAP)
OPINION
----------------------------**FILED UNDER
TEMPORARY SEAL**
----------------------------------------------------------(pending motion to seal)
PISANO, District Judge.
This is a Hatch-Waxman patent infringement action brought by Plaintiff Depomed,
Inc. (“Plaintiff” or “Depomed”) against defendants, Actavis Elizabeth LLC and Actavis Inc.
(together, “Defendant” or “Actavis”) in connection with Defendant’s filing of an
Abbreviated New Drug Application (“ANDA”) seeking approval to sell generic gabapentin
once-daily tablets. A bench trial was held May 12, 2014 to May 20, 2014, and the parties
presented evidence on the questions of whether Defendant infringes any of the asserted
claims in the seven patents-in-suit and whether the asserted claims are obvious and/or
indefinite. This Opinion constitutes the Court’s findings of fact and conclusions of law. As
set forth below, the Court finds that Plaintiff has shown by the preponderance of the
evidence that Defendant infringes the asserted claims, and further finds that Defendants
have not shown by clear and convincing evidence that the asserted claims are invalid.
A. THE PARTIES
Plaintiff Depomed Inc. is a corporation organized under the laws of California, with
a principal place of business in Newark, CA. Final Pretrial Order (“FPO”), Stipulated Facts
(“Stip. Facts”) ¶1. Depomed, a specialty pharmaceutical company, is the holder of New
Drug Application (“NDA”) No. 22-544, by which the United States Food and Drug
Administration (“FDA”) granted approval for tablets containing the active ingredient 1(aminomethyl) cyclohexaneacetic acid (known as “gabapentin”). Id. ¶ 2; Tr.1 373:8. These
gabapentin tablets are sold by Depomed in the United States under the brand name Gralise
in dosage sizes of 300 mg and 600 mg. Stip. Facts. ¶ 3. Gralise was approved by the FDA
for treatment of post-herpetic neuralgia (“PHN”). Id. ¶ 106. Presently, Gralise is the only
once-a-day gabapentin product indicated for PHN available in the marketplace that is
approved for commercial sale by FDA. Id. ¶ 107. Depomed began selling Gralise in or
about October of 2011. Id. ¶ 108.
Defendant Actavis LLC is a limited liability corporation organized and existing
under the laws of the State of Delaware, having a place of business in Morristown, New
Jersey. Id. ¶ 4. Defendant Actavis Elizabeth LLC is a limited liability company that is
wholly owned by Actavis LLC. Id. ¶ 5. Actavis Elizabeth LLC is organized and exists
under the laws of the State of State of Delaware, having a principal place of business in
Elizabeth, New Jersey. Id. On October 31, 2011, Defendant submitted ANDA No. 203611
with the FDA seeking approval to market generic gabapentin extended-release oral tablets
in dosage strengths of 300 mg and 600 mg (the “ANDA product”) prior to the expiration of
the patents-in-suit. Id. ¶ 14.
1
“Tr.” Refers to the transcript of the May 14-20, 2014 bench trial.
2
B. NATURE OF THE ACTION
The present action is for patent infringement under 35 U.S.C. § 271(e)(2)(A),
271(a), (b), and (c) and under the Hatch-Waxman Act, codified in part at 21 U.S.C. §
355(j). Defendant has counterclaimed for a declaration that it does not and will not infringe
any valid claim of the patents-in-suit, and for a declaration that patents-in-suit are invalid.
C. THE PATENTS-IN-SUIT
As set forth below, Depomed asserts against Actavis a number of composition and
method claims. These claims are directed to a type of extended-release gabapentin oral
dosage form that releases gabapentin in the stomach over several hours and delivers the
drug in such a way that an individual achieves certain blood concentrations of the drug and
that the drug has a therapeutic effect:
1. Platform/Gastric Retention Patent
a. U.S. Patent No. 6,635,280
United States Patent No. 6,635,280 (the “‘280 Patent”), entitled “Extending the
Duration of Drug Release Within the Stomach During the Fed Mode,” issued on October
21, 2003, to Depomed from a patent application filed on November 6, 2001, as a
continuation from United States Patent No. 6,340,475 (“the ‘475 Patent”). Stip. Facts ¶¶ 8,
50. FDA’s publication Approved Drug Products with Therapeutic Equivalence Evaluations
(commonly referred to as the “Orange Book”) identifies the expiration date of the ‘280
Patent as September 19, 2016. Id. at ¶ 8.
3
Depomed has asserted claims 1, 12, 14 and 45 of the ‘280 Patent in this case.2 Stip.
Facts ¶ 51.
Claim 1 of the ‘280 Patent is directed to:
A controlled release oral drug dosage form for releasing a drug whose
solubility in water is greater than one part by weight of said drug in ten parts
by weight of water, said dosage form comprising one or more polymers
forming a solid polymeric matrix with said drug incorporated therein at a
weight ratio of drug to polymer of from 15:85 to 80:20, said dosage form
being one that when swollen in a dimensionally unrestricted manner as a
result of imbibition of water is of a size exceeding the pyloric diameter in the
fed mode to promote retention in the stomach during said fed mode, that
releases said drug into gastric fluid by the dissolution and diffusion of said
drug out of said matrix by said gastric fluid, that upon immersion in gastric
fluid retains at least about 40% of said drug one hour after such immersion
and releases substantially all of said drug after such immersion, and that
remains substantially intact until substantially all of said drug is released.
Stip. Facts¶ 53, ‘280 Patent (JTX 2) at col. 17, ll. 45-61. Claims 12, 14, and 45 depend
from claim 1. Claim 12 adds the limitation that the “polymeric matrix is formed of
poly(ethylene oxide) at a molecular weight in the range of about 5,000,000 to about
8,000,000.” Stip. Facts. ¶ 59. Claim 14 adds the limitation that the “polymeric matrix upon
immersion in gastric fluid retains at least about 60% of said drug one hour after such
immersion.” Id. at ¶ 60. Claim 45 adds the limitation that the “dosage form releases
substantially all of said drug within about ten hours after immersion in gastric fluid.” Id. at
¶ 61.
2
With one exception noted infra, each of the patents-in-suit are being asserted against both dosage forms in
the ANDA, i.e., the 300mg and 600mg tablets.
4
2. Oval/Gastric Retention Patent
a. U.S. Patent No. 6,488,962
United States Patent No. 6,488,962 (the “‘962 Patent”), entitled “Tablet Shapes To
Enhance Gastric Retention of Swellable Controlled-Release Oral Dosage Forms”, issued to
Depomed as assignee of the inventors on December 3, 2002, from a patent application filed
on June 20, 2000. Stip. Facts ¶¶ 7, 40. The Orange Book identifies the expiration date of
the ‘962 Patent as June 20, 2020. Id. ¶ 7. Plaintiff’s product Gralise is an embodiment of
the asserted claims of the ‘962 Patent. Id. ¶ 111.
None of the four asserted claims from this patent have been asserted against
Defendant’s 300 mg dosage form; claims 5, 8, 10, and 13, from the ‘962 Patent are being
asserted against the 600 mg tablet only. Claims 5, 8, and 10 are dependent upon claim 1.
Claim 13 depends from Claim 10.
Independent claim 1 of the ‘962 patent reads as follows:
A controlled-release oral drug dosage form for releasing a drug into at least a
portion of a region defined by the stomach and the upper gastrointestinal
tract, said dosage form consisting essentially of a solid monolithic matrix
with said drug contained therein, said matrix being non-circular in shape and
having first and second orthogonal axes of unequal length, said matrix being
one that swells in an unrestricted manner along both such axes upon
imbibition of water, the longer such axis having a maximum length of 3.0
cm when said matrix is unswollen, and the shorter such axis achieving a
minimum length of 1.2 cm within one hour of immersion of said dosage
form in water and wherein said matrix has a shape which when projected
onto a plane, is either an oval or a parallelogram.
JTX 1 at col. 11, ll. 14-26, Stip. Facts ¶ 43. Claims 5, 8, and 10 add the following
limitations, respectively: (i) the dosage form where the “shorter axis has a length of 0.7 cm
to 1.5 cm when said matrix is unswollen”; (ii) the dosage form where the “longer axis has a
maximum length of 2.5 cm when said matrix is unswollen”; and (iii) where the “matrix is a
5
water-swellable polymer”. JTX 1 at col. 11, ll. 38-39, 47-48 and 53-54; Stip. Facts¶¶ 42,
46-48. Claim 13 depends from claim 10, and adds the following limitation: the dosage form
where the “water-swellable polymer is a member selected from the group consisting of
poly(ethylene oxide), hydroxypropylmethyl cellulose, and hydroxyethyl cellulose”. JTX 1
at col. 12, ll. 2-5; Stip. Facts ¶¶ 42, 49.
3. The Gabapentin Patents3
a. U.S. Patent No. 7,438,927
United States Patent No. 7,438,927 (the “‘927 Patent”), entitled “Methods of
Treatment Using a Gastric Retained Gabapentin Dosage,” issued to Depomed on October
21, 2008, from a patent application filed on October 25, 2002. Stip. Facts ¶¶ 9, 62. The
Orange Book identifies the expiration date of the ‘927 patent as February 26, 2024. Id. ¶ 9.
The use of Gralise in treating post-herpetic neuralgia (“PHN”) embodies the asserted claims
of the '927 Patent. Id. at ¶ 112.
Depomed has asserted claims 18, 25, 26, 34, 61 and 62 of the ‘927 Patent in this
action. Id. ¶ 63. Each of the asserted claims depend from either of two independent claims
– claim 17 (claims 18, 25, 26, 61) or claim 33 (claims 26, 62). Neither claim 17 or 33 is
asserted in this litigation.
Claim 17 of the ‘927 Patent is directed to:
A method of treating neuropathic pain in a mammal comprising
administering a therapeutically effective amount of a daily dosage of about
100 mg to about 4800 mg of gabapentin or a pharmaceutically acceptable
salt thereof, dispersed in a gastric retained dosage form to the mammal in
which a fed mode has been induced, wherein the dosage form comprises a
single polymer matrix comprising at least one swellable hydrophilic polymer
3
U.S. Patents No. 7,438,927, No. 7,731,989, No. 8,192,756, No. 8,252,332 and No. 8,333,992 are herein
referred to collectively as the “Gabapentin Patents.”
6
that swells in a dimensionally unrestrained manner by imbibing water to
increase its size to promote gastric retention of the dosage form in the
stomach of the mammal, and wherein upon contact with water, gabapentin is
released by diffusion from the dosage form over a period of at least five
hours and at least 40 wt% of the gabapentin is retained in the dosage form
one hour after administration.
JTX 3 at col. 12, ll. 38-51; Stip. Facts¶ 65.
Asserted claims 18, 25, 26, and 61 depend from claim 17 and, respectively, add the
following limitations: (i) the dosage form is administered once daily; (ii) the gastric
retained dosage form releases gabapentin to the stomach, duodenum and small intestine;
(iii) dosage form provides administration of at least 85 wt % of the gabapentin to be
delivered over a period of about 5-12 hours; and (iv) the mammal is a human.
Claim 33 of the ‘927 Patent reads as follows:
A method of administering a therapeutically effective amount of a daily
dosage of about 100 mg to about 4800 mg of gabapentin to a mammal,
comprising administering gabapentin or a pharmaceutically acceptable salt
thereof, dispersed in a gastric retained dosage form to the mammal in which
a fed mode has been induced, and wherein the dosage form comprises a
single polymer matrix comprising at least one swellable hydrophilic polymer
that swells in a dimensionally unrestrained manner by imbibing water to
increase its size to promote gastric retention of the dosage form in the
stomach of the mammal, and wherein upon contact with water, gabapentin is
released by diffusion from the dosage form over a period of at least five
hours and at least 40 wt% of the gabapentin is retained in the dosage form
one hour after administration.
JTX 3 at col. 12, l. 38; col. 13, ll. 25-39; Stip. Facts¶ 70.
Dependent claims 34 and 62, respectively, add the following limitations: (i) the
dosage form is administered once daily; and (ii) the mammal is a human. JTX 3 at col. 13,
ll. 40-41; col. 14, ll. 50-53; Stip. Facts ¶¶ 71, 72.
7
b. U.S. Patent No. 7,731,989
United States Patent No. 7,731,989 (the “‘989 Patent”), entitled “Gastric Retained
Gabapentin Dosage Form,” issued on June 8, 2010, to Depomed from a patent application
filed on September 26, 2008, as a continuation of the ‘927 Patent. Stip. Facts ¶¶ 10, 73.
The Orange Book identifies the expiration date of the ‘989 patent as October 25, 2022.
Stip. Facts¶ 10. Gralise is an embodiment of the asserted claims of the '989 Patent. Id. ¶
113.
Depomed has asserted claim 10 of the ‘989 Patent in this action. Stip. Facts ¶ 74.
Claim 10 depends from claim 1, which has not been asserted. Claim 1 of the ‘989 Patent
reads as follows:
A dosage form, comprising between about 100 mg to about 4800 mg of
gabapentin or pharmaceutically acceptable salt thereof, dispersed in a single
polymer matrix comprising at least one swellable hydrophilic polymer that
swells unrestrained dimensionally by imbibing water to increase its size to
promote gastric retention of the dosage form in a stomach in a fed mode,
wherein upon contact with water, gabapentin is released by diffusion from
the dosage form over a period of at least five hours and at least 40 wt % of
the gabapentin is retained in the dosage form 1 hour after administration.
JTX 4 at col. 12, ll. 9-18; Stip. Facts¶¶ 75-76. Claim 10 of the ‘989 Patent contains the
additional limitation that “the gabapentin has a bioavailability greater than or equal to 80%
of an equal dose of gabapentin in an immediate release dosage form.” JTX 4 at col. 12, ll.
37-39; Stip. Facts ¶ 77.
c. U.S. Patent No. 8,192,756
United States Patent No. 8,192,756 (the “‘756 Patent”), entitled “Gastric Retained
Gabapentin Dosage Form,” issued on June 8, 2010, to Depomed from a patent application
filed on May 19, 2011, as a continuation of the ‘927 Patent, Stip. Facts ¶¶ 11, 78, and
8
claims the same priority date of October 25, 2001, JTX3 at 1. Depomed has asserted claims
1, 2, 5, 6, 7 and 11 of the ‘756 Patent in this action. Stip. Facts¶ 79. The Orange Book
identifies the expiration date of the ‘756 patent as October 25, 2022. Gralise or its use in
treating PHN embodies the asserted claims of the '756 Patent. Id. ¶ 114.
Claim 1 of the ‘756 Patent is directed to:
A dosage form, comprising:
comprising from 100 mg to 4800 mg of therapeutically effective amount of
gabapentin or pharmaceutically acceptable salt thereof, dispersed in a single
matrix
wherein the matrix comprises at least one swellable hydrophilic polymer that
swells unrestrained dimensionally by imbibing water to increase its size to
promote gastric retention of the dosage form in the stomach in a fed mode,
wherein upon once-daily or twice-daily ingestion of the dosage form
gabapentin is released from the matrix over a period of at least five
hours wherein at least 40 wt% of the gabapentin is retained in the matrix one
hour after administration, and
wherein the gabapentin is released at a rate sufficient to achieve a lower
maximum plasma concentration (Cmax) compared to an equal dose of
gabapentin provided by an immediate release dosage form, and without loss
in bioavailability as measured by the area under the curve (AUCinfinity) as
compared to the bioavailability which is achieved from an immediate release
dosage form comprising the same dose of gabapentin.
JTX 5 at col. 12, l. 50 – col. 13, l. 3; Stip. Facts¶ 81.
Claims 2 and 5 depend from claim 1, and add the following limitations: (i) the time
to reach maximum plasma concentration is longer relative to the time to reach maximum
plasma concentration from an immediate release dosage form comprising the dose of
gabapentin; and (ii) the dosage form comprises a dose of gabapentin of between about 300600 mg. JTX 5 at col. 13, ll. 4-7, 12-13; Stip. Facts¶¶ 83, 84.
9
Claim 6 of the ‘756 Patent is similar to claim 1, however it is directed to a method
of treating a condition using the gabapentin-containing dosage form:
A method of treating a condition responsive to a therapeutic dose of
gabapentin, comprising:
orally administering once-daily or twice daily a dosage form comprising
between about 100 mg to about 4800 mg of gabapentin or pharmaceutically
acceptable salt thereof, dispersed in a single matrix,
wherein the matrix comprises at least one swellable hydrophilic polymer that
swells unrestrained dimensionally by imbibing water to increase its size to
promote gastric retention of the dosage form in the stomach in a fed mode,
wherein upon once-daily or twice daily ingestion of the dosage form
gabapentin is released from the matrix over a period of at least five hours
wherein at least 40 wt% of the gabapentin is retained in the matrix one hour
after administration, and
whereby the dosage form releases gabapentin at a rate sufficient to achieve a
lower maximum plasma concentration (Cmax) compared to an equal dose of
gabapentin provided by an immediate release dosage form, and without loss
in bioavailability as measured by the area under the curve (AUCinfinity) as
compared to the bioavailability which is achieved from an immediate release
dosage form comprising the same dose of gabapentin.
JTX 5 at col. 13, ll. 14-38.
Claim 7 and 11 depend from claim 6, and add the following limitations: (i) the time
to reach maximum plasma concentration is longer relative to the time to reach maximum
plasma concentration from an immediate release dosage form comprising the dose of
gabapentin; and (ii) the condition is neuropathic pain. JTX 5 at col. 14, ll. 1-4, 10-11.
d. U.S. Patent No. 8,252,332
United States Patent No. 8,252,332 (the “‘332 Patent”), entitled “Gastric Retained
Gabapentin Dosage Form,” issued on August 28, 2012, to Depomed from a patent
application filed on March 29, 2010, as a continuation of the ‘927 Patent. Stip. Facts ¶¶ 12,
88. Depomed has asserted claims 1, 6, 17, 22 and 24 of the ‘332 Patent. The Orange Book
10
identifies the expiration date of the '332 Patent as October 25, 2022. Id. ¶ 12. Gralise or its
use in treating PHN embodies the asserted claims of the ‘332 Patent. Id. ¶ 115.
Claim 1 of the '332 Patent reads as follows:
A dosage form, comprising a matrix comprising gabapentin, wherein upon
ingestion of the dosage form gabapentin is released from the matrix into the
upper gastrointestinal tract over about 5-12 hours at a rate sufficient to
achieve a lower maximum plasma concentration than that provided by an
immediate release dosage form comprising an equal amount of gabapentin,
and bioavailability of gabapentin is at least 80% of that provided by the
immediate release dosage form comprising an equal amount of gabapentin as
measured by the area under the plasma concentration-time curve, AUCinf·
JTX 6 at col. 12, ll. 12-22.
Claim 6 depends from claims 1, 4, and 5. Claim 4 is directed to “[t]he dosage form
of claim 1, wherein the matrix is a polymer matrix.” JTX 6 col 12, ll. 27-28. Claim 5 is
directed to “[t]he dosage form of claim 4, wherein the polymer matrix is comprised of a
swellable, hydrophilic polymer.” Id. ll. 29-30. Claim 6 is directed to “[t]he dosage form of
claim 5, wherein the gabapentin is released from the polymer matrix by diffusion.” Id. ll.
31-32.
Asserted claim 17 is a method claim which depends from claim 12. Claim 12 of the
‘332 patent reads as follows:
A method of treating a condition responsive to a therapeutic dose of
gabapentin, comprising: orally administering a dosage form, comprising a
matrix comprising gabapentin, wherein upon ingestion of the dosage form
gabapentin is released from the matrix into the upper gastrointestinal tract
over about 5-12 hours at a rate sufficient to achieve a lower maximum
plasma concentration than that provided by an immediate release dosage
form comprising an equal amount of gabapentin, and bioavailability of
gabapentin is at least 80% of that provided by the immediate release dosage
form comprising an equal amount of gabapentin as measured by the area
under the plasmaconcentration-time curve, AUCinf.
11
JTX6 at col 12, ll. 53-65. Claim 17 adds the limitation that the “condition is neuropathic
pain.” Id. col. 13, ll. 6-7.
Claim 22 of the ‘332 Patent is directed to:
A dosage form, comprising a matrix comprising gabapentin, wherein upon
ingestion of the dosage form gabapentin is released from the matrix into the
upper gastrointestinal tract over about 5-12 hours at a rate sufficient to
achieve a longer time to the maximum plasma concentration than that
provided by an immediate release dosage form comprising an equal amount
of gabapentin, and bioavailability of gabapentin is at least 80% of that
provided by the immediate release dosage form comprising an equal amount
of gabapentin as measured by the area under the plasma concentration-time
curve, AUCinf.
JTX 6 at col. 13, l. 21 - col. 14, l. 2.
Claim 24 of the ‘332 Patent is directed to:
A method of treating a condition responsive to a therapeutic dose of
gabapentin, comprising orally administering a dosage form comprising a
matrix comprising gabapentin, wherein gabapentin is released from the
matrix into the upper gastrointestinal tract over about 5-12 hours at a rate
sufficient to achieve a longer time to the maximum plasma concentration
than that provided by an immediate release dosage form comprising an equal
amount of gabapentin, and bioavailability of gabapentin is at least 80% of
that provided by the immediate release dosage form comprising an equal
amount of gabapentin as measured by the area under the plasma
concentration-time curve, AUCinf.
JTX 6 at col. 14, ll. 16-29.
e. U.S. Patent No. 8,333,992
The ‘992 Patent, entitled “Gastric Retained Gabapentin Dosage Form,” issued on
December 18, 2012, to Depomed from a patent application filed on July 27, 2012, as a
continuation of the ‘927 Patent. Stip. Facts ¶¶ 13, 99. The Orange Book identifies the
expiration date of the ‘992 Patent as October 25, 2022. Id. ¶ 13. Gralise or its use in
treating PHN embodies the asserted claims is an embodiment of the '992 Patent. Id. ¶ 116.
12
Depomed has asserted claims 1, 5 and 22 of the ‘992 Patent in this action. Stip.
Facts¶ 100.
Claim 1 of the ‘992 Patent is directed to:
A dosage form, comprising a matrix comprising gabapentin, wherein upon
ingestion of the dosage form by a human subject gabapentin is released from
the matrix into the upper gastrointestinal tract over about 5-12 hours at a rate
sufficient to achieve a lower maximum plasma concentration than that
provided by an immediate release dosage form comprising an equal amount
of gabapentin, and bioavailability of gabapentin is at least 80% of that
provided by the immediate release dosage form comprising an equal amount
of gabapentin as measured by the area under the plasma concentration-time
curve, AUCinf.
JTX 7 at col. 12, ll. 40-51; Stip. Facts ¶ 102.
Claim 5 depends from claim 4, which in turn depends from claim 1. Claims 4 and
5, respectively, add the limitations “wherein the matrix is a polymer matrix” and “wherein
the polymer matrix is comprised of a swellable, hydrophilic polymer.” JTX 7 at col. 12, ll.
56-59.
Asserted Claim 22 of the ‘992 Patent reads as follows:
A method of treating a condition responsive to a therapeutic dose of
gabapentin, comprising: orally administering to a human subject a dosage
form comprising a matrix comprising gabapentin, wherein gabapentin is
released from the matrix into the upper gastrointestinal tract over about 5-12
hours at a rate sufficient to achieve a longer time to the maximum plasma
concentration than that provided by an immediate release dosage form
comprising an equal amount of gabapentin, and bioavailability of gabapentin
is at least 80% of that provided by the immediate release dosage form
comprising an equal amount of gabapentin as measured by the area under the
plasma concentration-time curve, AUCinf.
JTX 7 at col. 14, ll. 13-26.
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D. WITNESSES AT TRIAL
The trial commenced with Plaintiff’s infringement case. For its infringement casein-chief, Depomed called five expert witnesses, Dr. Eden Tesfu, Dr. Gary Annunziata, Dr.
Hartmut Derendorf, Dr. Robert O. Williams, and Dr. Howard Hopfenberg.
Dr. Eden Tesfu, a former laboratory manager at Evans Analytical Life Sciences,
was accepted by the Court as an expert in analytical chemistry. Tr. 92:19-22. Dr. Tesfu
testified regarding swelling and dissolution studies performed on the Defendants’ proposed
ANDA product and Plaintiff’s Gralise tablet. Tr. 89-134.
Dr Gary Annunziata, a practicing gastroenterologist at the Eisenhower Medical
Center, Palm Springs, California, was accepted by the Court as an expert in stomach
physiology. Tr. 148:12-14. Dr. Annunziata testified with respect to the human pylorus and
the process of stomach digestion and emptying. Tr. at 141-168, 207- 260.
Dr. Hartmut Derendorf, a professor of pharmaceutics at the University of Florida,
was accepted as an expert in the field of pharmacokinetics by the Court. Tr. at 336:5–8.
Dr. Derendorf testified on the pharmacokinetic data from the Actavis ANDA and evidence
for gastric retention. Tr. at 332-367. Dr. Derendorf also provided testimony with respect to
the issue of obviousness. Tr. at 1022-1061.
Dr. Robert O. Williams, a professor at the University of Texas and a registered
pharmacist in the State of Texas, was accepted by the Court as an expert in the field of
formulation and pharmaceutical sciences. Tr. at 264:4–7. Dr. Williams testified as to the
ingredients and swelling properties of the proposed ANDA product and Gralise tablets. Tr.
at 260-309.
14
Dr. Harold Hopfenberg, a professor of chemical and biomolecular engineering at
North Carolina State University, was accepted by the Court as an expert in polymer science
and controlled release dosage forms. Tr. at 437:13-19. Dr. Hopfenberg testified as to the
shape and swelling of the Actavis ANDA product. Tr. at 431-494. Dr. Hopfenberg also
testified with respect the obviousness issues relating to the ‘962 Patent in Depomed’s
response case. Tr. at 931-955.
Plaintiff also presented the testimony of three fact witnesses with respect to the
issue of infringement, Mr. Jack Lee Anders, VP of Finance for Depomed Inc., Dr. Radi
Hejazi, Formulation Scientist at Actavis Elizabeth, and Dr. Meena Venugopal, former
employee at Actavis.
In response to Plaintiff’s infringement case, Defendant called one expert witness,
Dr. David Friend, director of product development at the CONRAD Program and associate
research professor of obstetrics and gynecology at Eastern Virginia Medical School. Dr.
Friend was accepted as an expert in the design and development of controlled release
dosage forms, design and development of gastric retained dosage forms, behavior of dosage
forms in the stomach during fed mode and the sizes and shapes of oral dosage forms. Tr.
498:9-12, 502:3-504:10. Dr. Friend testified as to the shape and swelling of Defendant’s
ANDA tablets. Tr. 497-547.
The trial then proceeded to the issue of validity. Defendant’s obviousness case-inchief was presented through two expert witnesses, Dr. Douglas Flanagan and Dr. Michael
Mayersohn, along with a fact witness by way of deposition testimony, inventor Dr. Sui
Yuen Eddie Hou (by video), a former Depomed employee and one of the named inventors
of the Gabapentin Patents.
15
Dr. Douglas R. Flanagan, a professor emeritus of pharmacy of the University of
Iowa and the chief scientific officer for the University of Iowa’s Pharmaceuticals
Development Consortium, was accepted as an expert in pharmaceutical formulation,
including the design and development of controlled release dosage forms. Tr. 549:20-22,
552:10-14. Dr. Flanagan provided testimony on the issue of obviousness with respect to all
of the Gabapentin Patents (‘927, ‘989, ‘756, ‘332, ‘992 Patents). Tr. 549-578, 608-687.
Dr. Michael Mayersohn, a professor of pharmaceutical sciences at the University of
Arizona, College of Pharmacy, was accepted as an expert on drug absorption and
pharmacokinetics. Tr. 688:14-15, 692:6-10. Dr. Mayersohn testified on the issue of
obviousness with respect to two of the Gabapentin Patents, the ‘332 and ‘992 Patents. Trial
Tr. 688-742.
In its response to Defendant’s obviousness case, Plaintiffs called experts Dr.
Howard Bockbrader, Dr. Barry Gidal, Dr. Michelle Brown, Dr. Howard Hopfenberg, Dr.
Linda Felton, Dr. Hartumut Derendorf, and Dr. Sean Nicholson. Plaintiff also presented
testimony by deposition of Dr. Andrew Johnson, Analytical Scientist for Actavis, regarding
his role in the development of the ANDA product. Tr. 1138:2-8.
Dr. Howard Bockbrader was accepted by the Court as an expert in the area of
clinical pharmacokinetics and in particular the pharmacokinetics of gabapentin. Trial Tr.
748:8-13. Dr. Bockbrader testified with respect to Warner-Lambert efforts to develop an
extended release gabapentin product and its opinion as to whether a gastric retained
gabapentin product could be developed. Tr. at 743-777. His testimony related to the ‘927,
‘989, ‘756, ‘332 and ‘992 Patents.
16
Dr. Barry Gidal was accepted by the Court as an expert on gabapentin
pharmacokinetics and pharmacodynamics. Trial Tr. 815:14-816:2. Dr. Gidal testified on
issues related to whether it was possible to develop a controlled-release gabapentin tablet.
Tr. at 811-865. His testimony related to the Gabapentin Patents.
Dr. Michelle Brown was accepted by the Court as an expert in the area of treating
neuropathic pain. Tr. at 869:4-20. Dr. Brown testified on the issue of long felt need for a
controlled-release gabapentin product and the manner in which Gralise is prescribed. Trial
Tr. at 866-893. Her testimony related to the Gabapentin Patents.
Dr. Linda Felton was accepted by the Court as an expert in controlled- release
dosage forms. Tr. at 959:1-4. Dr. Felton testified regarding non-obviousness of a
controlled-release gabapentin tablet. Tr. at 955- 1021. Her testimony related to the
Gabapentin Patents.
Dr. Sean Nicholson was accepted by the Court as an expert in the field of economics
in healthcare. Tr. at 1064:5-7. Dr. Nicholson testified as to his evaluation of the
commercial success of the Gralise product, the ‘962 Patent and the Gabapentin Patents. Tr.
at 1061-1099.
In rebuttal, Defendant called two expert witnesses, Dr. Raymond Sinatra and Dr.
Ryan Michael Sullivan.
Dr. Raymond Sinatra was accepted by the Court as an expert in pain medicine and
the prescribing practices of physicians in pain management. Tr. At 895:21-24. Dr. Sinatra
testified as to clinical trials performed on Gralise. Tr. at 893-908.
Dr. Ryan Michael Sullivan was accepted by the Court as an expert in the economics
of intellectual property as it pertains to pharmaceutical products. Tr. at 1165:25-1166:5.
17
Dr. Sullivan testified as to his evaluation of the commercial success of Gralise. Tr. at
1164-1201.
E. INFRINGEMENT
1. Legal Standards
If an ANDA seeks approval for a drug that is claimed in a patent or the use of which
is claimed in a patent, submission of the ANDA constitutes a statutory act of infringement
pursuant to § 271(e)(2) of the Patent Act. This section provides:
It shall be an act of infringement to submit an application under [section
355(j) of title 21] ... for a drug claimed in a patent or the use of which is
claimed in a patent ... if the purpose of such submission is to obtain approval
under such Act to engage in the commercial manufacture, use, or sale of a
drug, veterinary biological product, or biological product claimed in a patent
or the use of which is claimed in a patent before the expiration of such
patent.
35 U.S.C. § 271(e)(2)(A). In order make the infringement determination, a court conducts
a two-step infringement inquiry. First, the court construes the claims of the patent. Second,
the court compares the construed claims to the accused product and makes a determination
as to whether every claim limitation, or its equivalent, is found in the accused product.
Roche Palo Alto LLC v. Apotex, Inc., 531 F.3d 1372, 1377 (Fed. Cir. 2008). In the ANDA
context, the proper infringement inquiry focuses on the actual product that will enter the
market upon FDA approval. Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562, 1569 (Fed.
Cir. 1997) (court “must focus on what the ANDA applicant will likely market if its
application is approved”); Ben Venue Labs. v. Novartis Pharm. Corp., 146 F.Supp.2d 572,
579 (D.N.J. 2001) (“the statute requires that an infringement inquiry be focused on what is
likely to be sold following FDA approval”).
18
To prove infringement, the patentee must show that an accused product or method is
within the claim limitations of the patent-in-suit either literally or under the doctrine of
equivalents. See Amgen Inc. v. F. Hoffmann-LaRoche Ltd., 580 F.3d 1340, 1374 (Fed. Cir.
2009); Warner Jenkinson Co., Inc. v. Hilton Davis Chem. Co., 520 U.S. 17, 21 (1997).
Direct infringement requires a party to perform each and every step or element of a
claimed method or product. Cheese Systems, Inc. v. Tetra Pak Cheese and Powder
Systems, Inc., 725 F.3d 1341, 1348 (Fed. Cir. 2013). “If any claim limitation is absent from
the accused device, there is no literal infringement as a matter of law.” Bayer AG v. Elan
Pharm. Research Corp., 212 F.3d 1241, 1247 (Fed. Cir. 2000). If an accused product does
not infringe an independent claim, it also does not infringe any claim depending thereon.
See Wahpeton Canvas Co. v. Frontier, Inc., 870 F.2d 1546, 1553 (Fed. Cir. 1989).
Induced infringement, on the other hand, “requires that the alleged infringer
knowingly induced infringement and possessed specific intent to encourage another's
infringement.” DSU Med. Corp. v. JMS Co., 471 F.3d 1293, 1306 (Fed. Cir. 2006). The
induced infringement provision of the Patent Act, 35 U.S.C. § 271(b), provides that
“[w]hoever actively induces infringement of a patent shall be liable as an infringer.” “[T]he
sale of a product specifically labeled for use in a patented method constitutes inducement to
infringe that patent, and usually is also contributory infringement.” Eli Lilly & Co. v.
Actavis Elizabeth LLC, 435 Fed. App’x 917, 926 (Fed. Cir. 2011) (citing Astrazeneca LP v.
Apotex, Inc., 633 F.3d 1042, 1060 (Fed. Cir. 2010); DSU Med. Corp., 471 F.3d at 1305–06.
Thus, induced infringement under § 271(b) occurs where: (1) another party directly
infringes a patent claim; (2) the inducing party intentionally encourages the acts that
constitute such direct infringement; and (3) the inducing party knows that its actions will
19
cause direct infringement. See Global-Tech Appliances, Inc. v. SEB S.A., 131 S. Ct. 2060,
2068 (2011); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293,
1312 (Fed. Cir. 2005). To prove indirect infringement by the manufacturer of an allegedly
infringing product, a patentee must show that the manufacturer’s customers directly
infringe the patent. See Glenayre Elecs., Inc. v. Jackson, 443 F.3d 851, 858 (Fed. Cir.
2006). Induced infringement under 35 U.S.C. § 271(b) requires knowledge that the induced
acts constitute patent infringement. See Global-Tech, 131 S. Ct. at 2068.
Contributory infringement occurs if a party sells or offers to sell, a material or
apparatus for use in practicing a patented process, and that “material or apparatus” is
material to practicing the invention, has no substantial non-infringing uses, and is known by
the party “to be especially made or especially adapted for use in an infringement of such
patent.” 35 U.S.C. § 271(c). Contributory infringement exists where “it may be presumed
from distribution of an article in commerce that the distributor intended the article to be
used to infringe another's patent, and so may justly be held liable for that infringement.”
Metro–Goldwyn–Mayer Studios Inc. v. Grokster, Ltd., 545 U.S. 913, 932 (2005).
To establish contributory infringement, the patent owner must prove that: “(1) there
is direct infringement; (2) the accused infringer had knowledge of the patent at issue; (3)
the component has no substantial noninfringing uses; and (4) "the component is a material
part of the invention.” See Fujitsu Ltd. v. Netgear Inc., 620 F.3d 1321, 1326 (Fed. Cir.
2010).
An accused infringer’s knowledge of the patents may be demonstrated by an ANDA
filer’s certification and Notice Letter to the patent holder. Teva Pham. U.S.A., Inc. v.
Sandoz, Inc., 876 F. Supp. 2d 295, 349 (S.D.N.Y 2012).
20
In assessing whether an asserted noninfringing use is substantial, the factfinder
considers not only the use’s frequency, but also the use’s practicality, the invention’s
intended purpose, and the intended market. i4i Ltd. P'ship v. Microsoft Corp., 598 F.3d 831,
851 (Fed. Cir. 2010) aff'd, 131 S. Ct. 2238, 180 L. Ed. 2d 131 (2011). A substantial noninfringing use is one that is “not unusual, farfetched, illusory, impractical, occasional,
aberrant, or experimental.” Vita-Mix Corp. v. Basic Holding, Inc., 581 F.3d 1317, 1327
(Fed. Cir. 2009).
Plaintiff bears the burden of proving infringement and must meet its burden by a
preponderance of the evidence. See SmithKline Diagnostics, Inc. v. Helena Lab. Corp., 859
F.2d 878, 889 (Fed. Cir. 1988).
2. Direct Infringement
a. The ‘927, ‘989, and ‘756 Patents
Plaintiff alleges direct, literal infringement of the ‘927, ‘989, and ‘756 Patents.
With respect to infringement of these patents, there is a single claim element that is in
dispute, specifically, “swells … to increase its size to promote gastric retention.” The Court
has construed this claim element, which appears in several of the asserted patents, to mean
“such that when the dosage form is introduced into the stomach in the fed mode, the dosage
form remains in the stomach for several hours.” D.I. 251 at 6-11. Claims 18, 25, 26, 34, 61
and 62 of the ‘927 Patent, claims 1, 2, 5, 6, 7 and 11 of the ‘756 Patent and claim 10 of the
‘989 Patent each contain this claim element. Tr. 519:13-520:25. The Court finds that
Plaintiff has established by the preponderance of the evidence that Defendant’s ANDA
product meets this limitation.
21
of the destructive forces in the stomach during fed mode. Tr. 522:1-8. The Court credits
Dr. Williams testimony, however, stating that if the action of the stomach were grinding
down or breaking the ANDA products in vivo, it would result in a much faster release of the
gabapentin and change the pharmacokinetic data. Tr. 267:3-18; 302:15 – 303:5. That is, if
the dosage form were being ground down in vivo, the tablet would not have the ability to
release gabapentin over the extended period of five hours through the process of diffusion
as the parties have stipulated that it does in accordance with, e.g., claim 17 of the ‘927
Patent. Stip Facts at ¶¶ 5, 7 and 9; Tr. 267:3-18; JTX003, JTX004. Additionally, the
parties further stipulated that the ANDA products “remains substantially intact until
substantially all of said drug is released” as claimed in the ‘280 Patent. Stip. Facts ¶ 3;
JTX002.
Fifth, the Court finds credible the expert testimony of Dr. Williams who opined that
the ANDA products have “at least one swellable hydrophilic polymer that swells in a
dimensionally unrestrained manner by imbibing water to increase its size” as required by (i)
asserted claims 18, 25, 26, 34, 61 and 62 of the ‘927 Patent, (ii) asserted claims 1, 2, 5, 6, 7
and 11 of the ‘756 Patent, and (iii) asserted claim 10 of the ‘989 Patent. Tr. 268:10 –
269:14. This opinion is based on and is consistent with the findings above.
Sixth, the evidence shows that the swelling of the ANDA product promotes gastric
retention in the stomach. Dr. Annunziata provided testimony as to the workings of the
stomach in the fed mode, the state in which the stomach is to be in when the ANDA
product is taken. Upon the intake of food, the stomach enters the fed mode, during which
the stomach reduces large pieces of food into smaller pieces. Tr. 151:13-15. During fed
mode, the pH of the stomach changes and the stomach begins to contract. Tr. 152:14-18.
26
Waves of contractions start at the top (the fundus) and proceed through the stomach to the
antrum while the pylorus is clenched. Id. The pylorus retains large particles in the stomach
so that they can be further digested, and it allows smaller particles, those measuring about
2-4 mm, to pass through to the small bowel. Tr. 154:8-13, 217:16 – 218:4. The pylorus is
closed during the terminal antrum contraction and is open for brief periods of time during
the retropelling wave in which it opens like a relief valve to approximately 12.8
millimeters. Tr. 144:25 – 145:11, 155:10-18; 159:9-13, 233:18 – 234:1. The retropelling
wave pushes the remaining particles back up into the body of the stomach to then repeat the
process. Tr. 152:9 – 153:1, 153:13-15. The length of time the stomach is in fed mode
varies; fed mode may last anywhere between 45 minutes and six hours depending upon the
meal ingested. The average time is approximately four hours. Tr. 230:4-21.
According to Dr. Annunziata, it takes longer for meals of larger weight or higher
calorie content to empty from the stomach. Tr. 257:12-15; PTX000469. Indeed, the
density, weight, or shape of a particle may make it more difficult for that particle to exit the
stomach. Tr. 156:15–18. It logically follows, therefore, that a larger or swollen particle is
less likely it is to leave the stomach. Tr. 155:19-22, 156:4-11, 158:16-20, 209:5-21. Dr.
Annunziata explained that as a particle approaches the size of one centimeter, it becomes
very unlikely for it to leave the stomach through the pylorus. Tr. 156:4-11. A particle with
an elongated shape is likely to be repulsed from the pylorus when the stomach clenches and
is retropelled back into the stomach. Tr.156:15-23, 158:14-15. An increase in the mass of
a particle also makes it more likely to be retained. Tr. 218:20-22.
The above-referenced swelling studies show that the each of the ANDA product
tablets increases in both dimension and weight. Consequently, as the swelling tablet
27
approaches the pyloric channel it will tend to be retropelled, i.e., pushed back to the top of
the stomach when the pyloric channel clenches. Tr. 218:5-13. While a long tablet is likely
to be retained even when the pylorus is open because it may approach the pylorus sideways,
Tr. 219:1-10, the increase in size of the short axis also makes it less likely that the tablet
will pass through the pylorus, Tr. 219:11-16.
Seventh, according to the instructions on the ANDA product’s proposed label and
the pharmacokinetic data, a person of skill in the art would understand that the ANDA
tablets remain in the stomach for several hours. In this regard, some background as to how
gabapentin is absorbed by the body is useful. Studies have shown that gabapentin
absorption takes place in primarily in the small intestines. Tr. 339:11-16; PTX000500 at
Gralise_JDG_00000602. The Stevenson reference states “[c]omparison of the blood-level
data from oral and jejunal administration of gabapentin indicates that there is substantial
absorption from the duodenum and upper jejunum. Most important, gabapentin plasma
levels from colonic administration are substantially lower than those obtained from oral and
upper intestinal administration.” Tr. 339:17 – 340:2; PTX000500 at Gralise_JDG_
00000602.
Gabapentin “transporters,” which are proteins that “take up” the drug and move it to
the other side of the intestinal membrane, are located only in a small range of the small
intestine and, therefore, gabapentin must be “at the right place at the right time” in order to
be to be taken up. Tr. 338:5-13, 337:2 – 338:3. If the dosage form passes by the window of
absorption too rapidly (i.e., before the drug is released), the dosage form will not work well
because gabapentin will be released into the large intestine where it is not absorbed. Tr.
340:20-24.
28
Also, because gabapentin transporters are present in limited numbers, too much
drug saturates them, preventing further drug uptake. Tr. 339:3-8. Upon transporter
saturation, the uptake of gabapentin will no longer go up proportionately with an increase
of gabapentin dose. Although the amount of gabapentin provided may go up, the percent
absorption will go down. Tr. 341:14-24.
While gastric emptying time is affected by food, small intestinal transit time is not.
Tr. 344:3-13; Tr. 345:15 – 346:8; PTX000521 at DEPOACT0982017. It takes
approximately three hours for a dosage form to pass through the small intestines. Tr.
340:15-19; Tr. 343:12 – 344:10; PTX000525 at DEPOACT0981978-981980; 345:10-24;
PTX000521 at DEPOACT0982017.
In the case of a gastric-retained dosage form, the dosage form remains in the
stomach and releases the drug from that location. The drug moves down from the stomach
over a long period of time to the small intestine and can be absorbed by transporters there.
Tr. 338:23 – 339:2. Without gastric retention, the dosage form will leave the stomach
earlier and move into the small and large intestines. Thus, without gastric retention, there
would be a much earlier Tmax (i.e., time to maximum concentration of the drug in the
subject’s blood plasma, Tr. 315:20-24, 316:11- 14) and incomplete absorption because the
drug would be released when it is no longer able to be absorbed in the upper small
intestines. Tr. 349:2-14. With respect to gabapentin, gastric retention is essential for
sustained exposure of gabapentin to its site of absorption in the upper small intestines, and
this can be achieved by anchoring the dosage form in the stomach allowing the drug to
come out of the dosage form slowly over time. Tr. 344:18 – 345:6.
29
The proposed labeling for the ANDA products states “gabapentin should be titrated
to an 1800 mg dose taken orally once-daily with the evening meal. Gabapentin tablet
should be swallowed whole. Do not crush, split or chew the tablets.” PTX000136,
DEPOACT0321105. This labeling also states “[g]abapentin should be taken with evening
meals. If it is taken on an empty stomach, the bioavailability will be substantially lower.”
Id., DEPOACT0321123. Dr. Annunziata explained that one skilled in the art understands
that when medication is given during the evening meal, it is typically intended for the
dosage form to be retained in the stomach. Tr. 220:1-11. Medication given during fasting
state is generally expelled quickly from the stomach and, in the case of gabapentin, this
would limit its ability to be absorbed. Tr. 163:22 – 164:11.
The proposed labeling further states “gabapentin is absorbed from the proximal
small bowel by a saturable L amino transport system. Gabapentin bioavailability is not
dose proportional. As the dose is increased, bioavailability decreases.” PTX000136,
ACTGAB000321122. This informs one of skill that the drug ends up in and is absorbed at
the small bowel, which is the duodenum and upper jejunum, after being released from the
stomach where the dosage form resides. Tr. 165:10-21.
Thus, based on the label, a person of skill in the art would understand that if the
gabapentin tablet is given outside of a meal, it will leave the stomach during the digestive
process and therefore the gabapentin will not have time to be absorbed before it passes
through the area in the small bowel where it is absorbed. Tr. 164:12 – 165:1. The label’s
fed mode requirement, therefore, is an indication that the tablet is intended to stay in the
stomach. Tr. 217:6-15.
30
That the dosage remains in the stomach for several hours when administered
according to the fed requirement is shown by the pharmacokinetic data. Plaintiff’s expert
Dr. Derendorf, an expert in the area of pharmacokinetics, explained that pharmacokinetic
data shows that the ANDA products are retained in the stomach. Tr. 332-67. Defendant
had two bioequivalence studies performed on the 600 mg ANDA tablet that compared it to
Gralise--one study was done under fasting conditions while the other was done with the
stomach in fed mode. 315:2-8, 327:7 – 328:9; 319:13 – 320:1. Under fasting conditions
the 600 mg Actavis ANDA Product achieved an average Cmax (i.e., the maximum
concentration the drug reaches in blood plasma after administration) of 1.87 + 0.752 μg/ml
and the Gralise 600 mg product achieved a Cmax of 1.81 μg/ml. Tr. 316:16 – 317:7;
PTX000019 at ACTGAB000000555. In the fasted state the ANDA Product had a median
Tmax of four hours and Gralise 600 mg had a median Tmax of 3.5 hours. Tr. 317:21 – 318:1;
PTX000019 at ACTGAB000000555. The 600 mg ANDA Product had an AUC (i.e., “area
under the curve” measured from time zero to the last blood draw point of the study and
references the exposure of the drug in the subject, Tr. 316:3-7, 315:25 – 316:2) of 20.91 +
9.55 μg/ml and the Gralise 600 mg tablet had an AUC of 19.14 + 7.643 μg/ml. Tr. 318:918; PTX000019 at ACTGAB000000555.
Under fed conditions the 600 mg Actavis ANDA Product achieved a Cmax of 3.47 +
0.652 μg/ml and Gralise 600 mg tablets achieved a Cmax of 3.48 + 0.573 μg/ml. Tr. 320:215; PTX000020 at ACTGAB000000581. The median Tmax of the 600 mg Actavis ANDA
Product is 10 hours under fed conditions and the median Tmax of the Gralise 600 mg tablets
is 9 hours. Tr. 320:19-321:1; PTX000020 at ACTGAB000000581. Under fed conditions
31
the average AUC is 55.26 μg/ml for the 600 mg ANDA product and AUC is 52.20 μg/ml
for the Gralise 600 mg tablets. PTX0000020 at ACTGAB000000581.
Thus, test subjects given the 600 mg ANDA Product achieve a Cmax of 1.87 in
fasting, and this increased to 3.47 under fed conditions. Tr. 321:8-15. The median Tmax of
subjects given the 600 mg Actavis ANDA Product was 4 hours in fasting and 10 hours in
fed mode. Tr. 321:16-22. Overall, the results of the studies are consistent with the dosage
form being gastric retained during the fed mode. Tr. 349:18 – 350:16, 346:25 – 348:21;
PTX000506; 328:1-9; Tr. 348:22 – 349:14; 349:18 – 350:16; PTX000034; Tr. 327:11-22.
The data on 600 mg ANDA tablet data in fed conditions shows that there is drug coming
from the stomach over several hours, which is consistent with gastric retention of the
dosage form. Tr. 348:1-21; PTX0000034 at ACTGAB000008356.
Testing was also performed on the 300 mg ANDA product under fasting conditions
only, which indicated no gastric retention during such conditions. Tr. 326:17–25;
PTX000023 at ACTGAB000000659. Actavis submitted a waiver for 300 mg fed studies
indicating that the it was not necessary because the once daily 300 and 600 mg tablets are
proportionally similar, Tr. 356:3–18, and pointing out that that the 300 and 600 mg ANDA
tablets have dissolution rates that are similar to the Gralise 300 and 600 mg tablets. Tr.
356:21–357:13.
Dissolution studies show that the ANDA products have the same dissolution rates
and pharmacokinetics as the Gralise tablets, which the parties agree are embodiments of the
‘927, ‘989 and ‘756 Patents and are gastric retained. Tr. 357:3-359:20; PTX 12. That the
ANDA products have the same dissolution rates and pharmacokinetics as the Gralise tablets
is indicative of these tablets having the same mechanisms (e.g., gastric retention, absorption
32
rates), otherwise differences in the blood levels or dissolution rates would be seen. Tr.
357:17– 359:2.
Finally, the Court credits the testimony of Drs. Derendorf and Annunziata, who
based on the foregoing, opined that the ANDA products increase its size to promote gastric
retention of the dosage form within the meaning of the asserted claims of the ‘756, ‘927 and
‘989 Patents. Tr. 336:20 – 337:6, 359:3-19; 162:1-10; 217:1-5; 219:17 – 221:18.
Defendant argues that evidence merely showing gastric retention of the ANDA
tablets does not show that there has been the required swelling of the tablet in the stomach,
as Defendant contends there is evidence that something other than swelling causes the
ANDA product to remain in the stomach. E.g., Tr. 235:9-19 (small particles can be
retained in the stomach); 129:22-25; PTX 332 at DEPOACT0975179.1 (ANDA tablets
began floating during testing). However, the Court finds that the preponderance of the
evidence set forth above shows that Defendant’s ANDA product “swells … to increase its
size to promote gastric retention,” as that term has been construed by this Court.
Consequently, based on the foregoing, the Court concludes that a preponderance of the
evidence shows that Defendant’s 300 mg and 600 mg ANDA products will, if produced and
marketed, directly infringe claim 10 of the ‘989 Patent; claims 1, 2, and 5 of the ‘756
Patent; claims 1, 6 and 22 of the ‘332 Patent; and claims 1 and 5 of the ‘992 Patent.
b. The ‘280 Patent
Actavis has stipulated that its 300 mg and 600 mg ANDA products meets all the
elements of the asserted claims except one. Claim 1 of the ‘280 Patent requires that “said
dosage form being one that when swollen … is of a size exceeding the pyloric diameter in
the fed mode to promote retention in the stomach during said fed mode.” JTX 2 at col. 17,
33
ll. 53-55; Stip. Facts¶ 53. Claims 12, 14, and 45 are dependent upon claim 1. JTX 2; Stip.
Facts¶ 52. Thus, claims 1, 12, 14, and 45 of the ‘280 Patent require that the “dosage form
… when swollen” be “a size exceeding the pyloric diameter in the fed mode to promote
retention in the stomach during said fed mode.” Defendant first argues that this claim is
indefinite, and for the reasons set forth in a later section of this opinion, the Court finds that
it is not indefinite. The parties also dispute, if not indefinite, whether this limitation is met.
The person of ordinary skill in the art understands the claim phrase “said dosage
form being one that when swollen” in Claim 1 of the ‘280 Patent to mean that the claimed
dosage form swells by the imbibition of water so that it increases in size. Tr. 455:3-23.
There appears to be little dispute in that regard. And as noted earlier, the Court has
construed “is of a size exceeding the pyloric diameter in the fed mode to promote retention
in the stomach during said fed mode” to mean “such that when the dosage form is
introduced into the stomach in the fed mode, the dosage form remains in the stomach for
several hours.” D.I. 251 at 8-9.
As to the first portion of the disputed claim limitation, the evidence shows that the
ANDA products swell. The Court discusses swelling above. Based upon his analysis of
the Actavis product label, in vitro swelling studies conducted on the 300 mg and 600 mg
ANDA products, and stipulations by Defendants that drug release from the ANDA dosage
forms is controlled by diffusion, Dr. Hopfenberg credibly opined that the Actavis ANDA
products swell and, therefore, satisfy the requirement “said dosage form being one that
when swollen” in Claims 1, 12, 14, and 45 of the ‘280 Patent. Tr. 453:8 – 454:14; 457:1–
464:5; PTX000135; PTX000136; PTX000238.
34
Based upon an analysis of the Actavis product label and multiple in vitro swelling
studies conducted on the 300 mg and 600 mg ANDA products, Dr. Annunziata credibly
opined that the ANDA products will remain in the fed stomach for several hours following
ingestion. Tr. 222:4 – 223:10; PTX000135; PTX000136; PTX000238. Dr. Derendorf
testified, based upon his analysis of pharmacokinetic data obtained from Gralise and from
the 300 mg and 600 mg Actavis ANDA products, that the ANDA products are gastric
retained within the meaning of the asserted claims of the ‘280 Patent. Tr. 349:18 – 351:16,
354:9 – 356:2, 357:17 – 359:2, 359:20-22.
Defendant argues that its ANDA products do not infringe because Plaintiff has
failed first to established that the ANDA products swell and, second, that even if there was
proof of swelling, there is no evidence that such swelling exceeds the size of the pyloric
diameter.5
As to Defendant’s first argument, the Court has concluded, supra, that the evidence
establishes that Defendant’s ANDA products swell. Defendant’s second argument also
fails in that it ignores the claim construction adopted by the Court. In any event, even if a
size limitation were considered, the evidence shows that it is more likely than not that the
ANDA products swell to a size that exceed the pyloric diameter. Actavis reported swelling
data to the FDA showing that its tablets swell in vitro in simulated gastric fluid:
5
Pyloric diameter here refers to those periods that the pylorus relaxes to allow larger materials to escape the
stomach, and not the periods of time during which the pylorus is clenched tightly closed to prevent the
stomach contents from being expelled into the intestines.
35
300 and 600 mg tablets exceed these measurements, in the fed mode, which testimony
shows could be up to three or four hours or more. Tr. 230:4-21; 532:11-15.
Finally, Defendant contends there is no infringement with regard to the 600 mg
tablet because it notes that the dry tablet starts out at a size larger than the pyloric diameter
and, therefore, swelling is not responsible for its dimensions being larger than the pyloric
diameter. Without finding whether the 600 mg tablet does or does not have a dry
measurement that exceeds the pyloric diameter, the Court finds that even if it did, there is
no claim requirement that the dosage form start out at any particular size. There is only the
requirement that its swollen size is larger than the pyloric diameter to promote the dosage
form remaining in the stomach for the duration of the fed mode.
Consequently, the Court concludes that Plaintiff has established by the
preponderance of the evidence that Defendant’s 300 mg and 600 mg ANDA products meet
the limitations of the “when swollen . . . to promote retention in the stomach during said fed
mode” element of Claim 1 of the ‘280 Patent. As such, given the parties’ stipulations as to
the other claim elements, the Court finds that Defendant’s 300 mg and 600 mg ANDA
products will, if produced and marketed, directly infringe Claims 1, 12, 14, and 45 of the
‘280 Patent
c. The ‘962 Patent (Oval)
Depomed asserts the ‘962 Patent against Actavis’s 600 mg ANDA product, not its
300 mg ANDA product. There is only one claim element in dispute with respect to the
‘962 patent: claims 5, 8, 10 and 13 of the ‘962 Patent all require that the dosage form have
“a shape which when projected onto a plane, is either an oval or a parallelogram.” As
37
Depomed has not asserted that Actavis’s tablet is a parallelogram, the infringement dispute
centers on whether the 600 mg ANDA product is an “oval.”
The parties have agreed that the term “an oval” is to be construed as “any curve that
is closed and concave towards the center wherein the geometric form bounded by the closed
curve has a first and second orthogonal axes of unequal length.” Stip. Facts ¶ 44. Dr.
Hopfenberg explained this construction. He testified that a POSA would understand a
“closed” curve as one that goes around and turns back on itself, Tr. 442:1-6., a “concave”
curve as a line that is concave toward a center point in, for example, a matrix dosage form,
Tr. 442:10-21, and that “first and second orthogonal axes of unequal length” are
perpendicular to each other, Tr. 444:7-13. He explains credibly that a POSA would
understand an axis as a line of symmetry that divides a two-dimensional shape or object
into symmetrical halves. Tr. 443:3-22.
The following is a photograph of the 600 mg ANDA product:
PHYJTX 2.
38
The drawing for the punches used to make the tablets show the profile for the tablet:
PTX 57.
Dr. Hopfenberg testified that the above diagram of the punch used by Actavis for
the 600 mg ANDA tablets shows a closed curve, concave toward the center with a first and
second orthogonal axis of unequal lengths (orthogonal axes are designated by the CL),
therefore, it satisfies the agreed construction of “an oval.” Tr. 445:22 – 446:7, 450:2-12;
PTX000057. Exemplar samples of the 600 mg ANDA product match the shape shown in
the punch diagram. PHYJTX 2; PTX 56; PTX 57. Dr. Hopfenberg also concluded that an
exemplar sample of the 600 mg ANDA product projects an oval consistent with the agreed
construction of “an oval.” PHYJTX 2.
Depomed also points out that Actavis on at least one occasion referred to its ANDA
product as oval shaped. Actavis formulation scientist, Radi Hejazi, issued a purchase
request for 27 tablet dies to be used to manufacture the 600 mg ANDA product. Tr. 78:24 –
39
79:22, 87:24 – 88:1; 446:15-19; 447:6-16; PTX000043; PTX000044, PTX000057. In the
body of the purchase order, Dr. Hejazi described the requisitioned punch as specific-sized
“Oval Shape Embossed with 4132.” Tr. 79:16-18; PTX000044 (emphasis supplied).
While certainly far from dispositive, the Court does find the fact that an Actavis employee
referred to the 600 mg ANDA product as an “oval” to have some relevance to its inquiry.
Dr. Friend testified in response to Plaintiff’s infringement case-in-chief. Contrary to
Dr. Hopfenberg’s opinion, Dr. Friend, relying on tableting literature, testified that the 600
mg ANDA product is not an oval but is rather a “modified capsule.” Tr. 511:12-18. In
reaching this conclusion, however, Dr. Friend concedes that he did not apply the parties’
agreed-upon claim construction of “oval” because he found it confusing and unclear. Tr.
513:17-20. He further stated that he did not apply the agreed-upon construction because,
specifically with respect to the phrase “geometric form bounded by a closed curve,” he
found it could apply to other tablet shapes as well, specifically almond. Dr. Hopfenberg
disputes this. Tr. 480:8 – 482:6, 492:2-9. Dr. Friend also disagrees with Dr. Hopfenberg’s
definition of the term axis, disagreeing specifically with Dr. Hopfenberg’s testimony that
symmetrical halves are required for two-dimensional objects.
The Court gives Dr. Friend’s testimony regarding infringement of the ‘962 patent
little, if any, weight. As a general matter, based on the Court’s consideration of the content
of his testimony and the Court’s own observation of the witness’ demeanor, the Court finds
him to be a less credible witness than Dr. Hopfenberg. Thus, where their testimony is at
odds, the Court credits Dr. Hopfenberg’s testimony over that of Dr. Friend.
Here, the parties stipulated to a claim construction and advised the Court of their
agreement. D.I. 188 (Joint Claim Construction and Prehearing Statement). Yet Dr. Friend
40
(and Defendants) chose to ignore that construction. Indeed, the Court finds no reference to
it in Defendant’s post trial submission. While they do not expressly offer an alternative
construction, Dr. Friend’s testimony makes clear that he is substituting the definition of
“oval” set forth in the certain tableting literature for the construction agreed to by the
parties. In their post-trial submission, Defendants in effect ask the Court to adopt that new
construction.
The Local Patent Rules, however, set forth the procedure for parties to follow to
resolve claim construction disputes. Following these procedures earlier in this litigation,
the parties advised the Court that they had agreed on a construction for “oval.” D.I. 188
(Joint Claim Construction and Prehearing Statement). Defendant never advised the Court
of any change and never sought to withdraw from that stipulation. Defendants, therefore,
are estopped from arguing for a different construction at trial.
Further, to the extent that the Court would be required to construe the term “oval,” it
would adopt the stipulated construction. Based on Dr. Hopfenberg’s testimony, the Court
rejects Defendant’s contentions that the stipulated construction is at odds with the intrinsic
evidence. Furthermore, the stipulated construction is identical to the Court’s prior
construction of this term in Depomed, Inc. v. Sun Pharma Global FZE, 2012 WL 3201962
*15 (D.N.J. 2012), and there has been no credible evidence presented that compels a
different construction.
Applying the proper construction within the appropriate analysis, the Court
concludes based upon the findings above that the 600 mg ANDA product literally infringes
the “wherein said matrix has a shape which when projected onto a plane, is either an oval or
a parallelogram” element of claim 1 of the ‘962 Patent. Actavis has stipulated to
41
infringement of all other elements of the asserted claims of the ‘962 Patent. Consequently,
the Court finds that the 600 mg ANDA product will, if produced and marketed, directly
infringe asserted Claims 5, 8, 10, and 13 of the ‘962 Patent.
3. Indirect infringement
Claims 18, 25, 26, 34, 61 and 62 of the ‘927 Patent, claims 6, 7 and 11 of the ‘756
Patent, claims 17 and 24 of the ‘332 Patent and claim 22 of the ‘992 Patent are directed to
methods of treatment involving administration of a gastric retained dosage form comprising
gabapentin. Plaintiff asserts indirect infringement against Actavis with respect to these
claims, specifically, that Actavis contributorily infringes or induces the infringement of
these claims.
a. Contributory Infringement
The Court finds that Depomed has shown by the preponderance of the evidence that
Actavis will contribute under 35 U.S.C. § 271(c) to the infringement of the asserted method
claims of the ‘927, ‘756, ‘332 and ‘992 patents. As an initial matter, the Court finds that
physicians and patients will directly infringe the asserted method claims. The proposed
Actavis ANDA label instructs that “Gabapentin is a prescription medicine used in adults 18
years and older to treat pain from damaged nerves, (neuropathic pain) that follows healing
of shingles, a painful rash that comes after a herpes zoster infection” which is otherwise
known as postherpetic pain, a type of neuropathic pain. PTX000136 at
ACTGAB000321131; Tr. 290:1-10. The dosage form will be administered by a healthcare professional following the label’s method of treating, which is the same as used in the
Gralise label. Tr. 285:5-8, 305:6-11. For the reasons stated above, these acts will directly
infringe the asserted gabapentin patent claims.
42
Second, Actavis had knowledge of the patents at issue as evidenced by their
submission of a Paragraph IV certification to FDA and notice to Depomed. Stip Facts ¶¶
15, 16, and 18-22.
Third, the ANDA product may not be marketed for non-infringing uses. Drug
companies are not permitted to promote their products for anything other than what is
approved in the label. Tr. 288:10–20. The label provided by Actavis indicates that it may
be used only for the management of postherpetic neuralgia, which is a form of neuropathic
pain and a therapeutic use. Tr. 289:2-10; 289:23 – 290:10; PTX000136 at
ACTGAB000321105. Defendant argues that this element of the contributory infringement
analysis (i.e., that there are not significant noninfringing uses) has not been met due the
existence of a number of off-label uses exist for the ANDA. However, because Actavis
cannot expressly market its product for any of these uses, the Court finds this third element
to be met.
Fourth, the Actavis 300 and 600 mg dosage forms are a material part of the ‘927,
‘756, ‘332 and ‘992 Patent method claims because the methods require the administration
of gabapentin in a therapeutically effective amount, for the purposes of treating neuropathic
pain or postherpetic neuralgia, or diseases responsive to a therapeutic dose of gabapentin.
Tr. 283:9–284:13; 285:3–8; 285:18–286:14; 287:15–20. Actavis has stipulated that the
ANDA products meet these elements. Stip. Facts¶¶ 5, 9, 11, 13. The asserted method
claims of the patents generally require gastric retained dosage forms with single polymer
matrices made up of at least one swellable hydrophilic polymer that swells in size and
dimensions in an unrestrained manner and release drug by diffusion over at least five hours.
43
Tr. 284:4-13. Actavis has stipulated that it meets these elements as well. Stip. Facts ¶¶ 5, 9,
11, 13. Thus, the ANDA products factually constitute a material part of the method claims.
All elements of the claim having been met, the Court finds that Actavis will
contribute to the infringement of the asserted method claims of the ‘927, ‘756, ‘332 and
‘992 patents it its ANDA products are produced and marketed.
b. Induced Infringement
Likewise, the Court finds that Defendant will induce infringement of the asserted
method claims. First, as discussed above, there will be direct infringement of the asserted
claims. Further, Actavis will knowingly and intentionally induce infringement of the ‘927,
‘756, ‘332 and ‘992 Patents. Actavis had knowledge of the patents at issue as evidenced by
their submission of a Paragraph IV certification to FDA. Stip Facts ¶¶ 15, 16, and 18-22.
Further, Actavis agrees that the ANDA products meet the relevant elements of the asserted
method claims of these patents. Stip. Facts ¶¶ 5, 9, 11, 13. Actavis also agrees that the
Gralise tablets are embodiments of the asserted method claims. Tr. 272:12–273:23;
PTX000014 at ACTGAB000000336; Stip. Facts ¶¶ 111-116. The ANDA dosage form will
be administered by a health-care professional or user following the label’s method of
treating, which is the same as used in the Gralise label. Tr. 285:5-8, 305:6-11; see DTX 31.
Both labels instruct the user that the gabapentin tablets are to be “taken orally, once- daily,
with the evening meal.” PTX 136 at ACTGAB000321105. Gabapentin is approved for the
treatment of postherpetic neuralgia. Tr. 883:20-884:9. The label for the ANDA product
that it is to be used for the management of postherpetic neuralgia, a form of neuropathic
pain and a therapeutic use. Tr. 289:2–10; 289:23 – 290:10; PTX000136 at
ACTGAB000321105. See Astrazeneca LP v. Apotex, Inc., 633 F.3d 1042, 1060 (Fed. Cir.
44
2010) (product label authorizing the patented use was evidence of affirmative intent to
induce infringement because it “would inevitably lead some consumers to practice the
claimed method”).
F. OBVIOUSNESS
1. Burden of Proof
An obviousness analysis starts from the presumption that the challenged patent is
valid, as every claim of a duly issued patent is accorded a statutory presumption of validity.
See 35 U.S.C. § 282. As such, parties challenging the validity of a patent must prove
invalidity by clear and convincing evidence. See id.; Microsoft Corp. v. i4i Ltd.
Partnership, 131 S.Ct. 2238, 2243, 180 L.Ed.2d 131 (2011); Innovative Scuba Concepts,
Inc. v. Feder Indus., Inc., 26 F.3d 1112, 1115 (Fed. Cir. 1994). Clear and convincing
evidence is a higher burden of proof than preponderance of the evidence. See Colorado v.
New Mexico, 467 U.S. 310, 316, 104 S.Ct. 2433, 81 L.Ed.2d 247 (1984). To be clear and
convincing, evidence must “place[ ] in the factfinder ‘an abiding conviction that the truth of
[the] factual contentions are highly probable.’ ” Procter & Gamble Co. v. Teva Pharma.
USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009) (quoting id.)). Clear and convincing
evidence should “instantly tilt[ ] the evidentiary scales” in favor of its proponent when
weighed against the opposing evidence. Colorado v. N.M, 467 U.S. at 310.
2. Applicable Legal Standards
“A patent may not be obtained ... if the differences between the subject matter
sought to be patented and the prior art are such that the subject matter as a whole would
have been obvious at the time the invention was made to a person having ordinary skill in
the art to which said subject matter pertains.” 35 U.S.C. § 103(a). “The [obviousness]
45
analysis is objective” and judged as of the “time the invention was made.” KSR Int'l Co. v.
Teleflex Inc., 550 U.S. 398, 406, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007) (citation omitted).
The ultimate determination of obviousness is a question of law based on underlying
factual findings, including the level of ordinary skill in the pertinent art; the scope and
content of the prior art; the differences between the claimed invention and the prior art; and
objective indicia of nonobviousness, i.e., evidence of factors such as whether the claimed
invention is a commercial success, provides unexpected benefits, satisfies a long-felt need,
or succeeds where others have failed. See id.; see also Graham v. John Deere Co., 383
U.S. 1, 17–18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966) ( “[Obviousness] lends itself to several
basic factual inquiries. Under § 103, the scope and content of the prior art are to be
determined; differences between the prior art and the claims at issue are to be ascertained;
and the level of ordinary skill in the pertinent art resolved. Against this background, the
obviousness or nonobviousness of the subject matter is determined.”). While party
defending a patent may offer evidence of secondary considerations of nonobviousness,
secondary considerations of nonobviousness may not overcome a strong prima facie case of
obviousness. Wyers v. Master Lock Co., 616 F.3d 1231, 1246 (Fed. Cir. 2010).
Notably, “the results of ordinary innovation are not the subject of exclusive rights
under the patent laws.” KSR, 550 U.S. at 427. Where the issue of obviousness is based on
a combination of elements found in the prior art, “the combination must do more than yield
a predictable result.” Id. at 416. In fact, “a combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield predictable results.”
Id. This is because “[g]ranting patent protection to advances that would occur in the
ordinary course without real innovation retards progress and may, in the case of patents
46
combining previously known elements, deprive prior inventions of their value or utility.”
Id. at 419. “In other words, obviousness exists when ‘a finite, and in the context of the art,
small or easily traversed number of options ... would convince an ordinarily skilled artisan
of obviousness.’ ” Purdue Pharma Products L.P. v. Par Pharmaceutical, Inc., 642
F.Supp.2d 329, 368 (D. Del 2009) (quoting Ortho–McNeil Pharm., Inc. v. Mylan Labs.,
Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008)).
Importantly, “a patent composed of several elements is not proved obvious merely
by demonstrating that each of its elements was, independently, known in the prior art.”
KSR, 550 U.S. at 418. Rather, the party challenging validity must show that a person of
ordinary skill in the art “would have been motivated to combine the teachings of the prior
art references to achieve the claimed invention, and ... would have had a reasonable
expectation of success in doing so.” Procter & Gamble, 566 F.3d at 994 (quoting Pfizer,
490 F.3d at 1361). The skilled artisan would interpret prior art references “using common
sense and appropriate perspective.” Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352,
1360 (Fed. Cir. 2011).
The obviousness standard is a somewhat flexible one. The Supreme Court has held
that a patent may be obvious in light of the combination of prior art if the combination was
“obvious to try.” Id. at 421. This flexible standard expands the obviousness analysis
beyond just “published articles and the explicit content of issued patents.” Id. at 419. Other
forces, including forces such as market demand, may also be examined to determine
whether it would be obvious to combine more than one known element. Id. In broad terms,
“any need or problem known in the field of endeavor at the time of the invention and
addressed by the patent can provide a reason for combining the elements in the manner
47
claimed.” Id. at 420. The Federal Circuit has noted that a finding of obviousness “does not
require absolute predictability of success ... all that is required is a reasonable expectation
of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009) (quoting In re O'Farrell,
853 F.2d 894, 903–04 (Fed. Cir. 1988)); Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157,
1165 (Fed. Cir. 2006) (same); see also Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364
(Fed. Cir. 2007) (“[T]he expectation of success need only be reasonable, not absolute” nor
“a guarantee.”).
In conducting the obviousness analysis, the claimed invention must be viewed in
light of the art that existed at the time the invention was made. See 35 U.S.C. § 103(a);
Uniroyal, 837 F.2d at 1050–51. “The term ‘prior art’ as used in section 103 refers at least to
the statutory material named in 35 U.S.C. § 102” that was available to a hypothetical person
of skill in the art at the time the invention was made. Riverwood Int'l Corp. v. R.A. Jones &
Co., Inc., 324 F.3d 1346, 1354 (Fed. Cir. 2003). “To ascertain the scope of the prior art, a
court examines the field of the inventor's endeavor and the particular problem with which
the inventor was involved.” Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH, 139
F.3d 877, 881 (Fed. Cir.1998) (citations and internal quotes omitted).
What a reference teaches is a question of fact. In re Bell, 991 F.2d 781, 784 (Fed.
Cir. 1993). The Court should not “analyze each prior art reference in isolation without
considering the prior arts' teaching as a whole in light of the creativity and common sense
of a person of ordinary skill.” Duramed Pharms., Inc. v. Watson Labs., Inc., 2011 WL
1086573, at *4 (Fed. Cir. Mar.5, 2011). Importantly, the Federal Circuit has admonished
against the use of the claimed invention to define the prior art:
48
Defining the problem in terms of its solution reveals improper hindsight in
the selection of the prior art relevant to obviousness .... By importing the
ultimate solution into the problem facing the inventor, the district court
adopted an overly narrow view of the scope of the prior art. It also infected
the district court's determinations about the content of the prior art.
Monarch Knitting, 139 F.3d at 881 (citations omitted).
All teachings in the prior art must be considered in the obviousness determination,
“including that which might lead away from the claimed invention.” In re Dow Chem. Co.,
837 F.2d 469, 473 (Fed.Cir.1988). “[A] reference must be considered as a whole, including
the portions that argue against or teach away from the claimed invention.” Armament Sys.
& Procedures, Inc. v. Monadnock Lifetime Prods., Inc., 1998 WL 537746, at *8 (Fed. Cir.
Aug.7, 1998) (citing Bausch & Lomb, 796 F.2d at 448). “Where the prior art contains
apparently conflicting teachings (i.e., where some references teach the combination and
others teach away from it) each reference must be considered for its power to suggest
solutions to an artisan of ordinary skill[,] considering the degree to which one reference
might accurately discredit another.” Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165
(Fed.Cir.2006) (citation and internal quotes omitted).
Courts are warned against improperly using hindsight in the obviousness analysis.
It is impermissible to use “hindsight reconstruction of references to reach the claimed
invention without any explanation as to how or why the references would be combined to
produce the claimed invention.” Innogenetics, N.V. v. Abbott Laboratories, 512 F.3d 1363,
1374 n. 3 (Fed. Cir. 2008); see also KSR, 550 U.S. at 421; In re Dembiczak, 175 F.3d 994,
999 (Fed. Cir. 1999) (“Measuring a claimed invention against the standard established by
section 103 requires the oft-difficult but critical step of casting the mind back to the time of
invention, to consider the thinking of one of ordinary skill in the art, guided only by the
49
prior art references and the then-accepted wisdom in the field.”), abrogated on other
grounds, In re Gartside, 203 F.3d 1305 (Fed. Cir. 2000). “A factfinder should be aware ...
of the distortion caused by hindsight bias and must be cautious of arguments reliant upon ex
post reasoning.” KSR, 550 U.S. at 421.
3. Person of Ordinary Skill in the Art
Defendant’s expert Dr. Flanagan defined a person of ordinary skill in the art
(“POSA”) as “a person with a Ph.D. in chemistry, chemical engineering, pharmaceutical
sciences or a related discipline. Alternatively, the person could have a master’s degree in
one of those fields with at least two years of practical experience and alternatively, the
person could have a bachelor’s degree in one of those fields with even more practical
experience.” Tr. 553:17-24.
Plaintiff’s expert Dr. Hopfenberg proffered a slightly different definition of a person
of ordinary skill in the art: “the person of ordinary skill … would have formal education, at
least a bachelor degree in the field of chemistry, chemical engineer, pharmaceutical science
and/or material science, the focus on polymer science and having substantial experience in
the development of controlled-release drug dosage forms.” He further opined that if this
person had a Ph.D., then only two years of industry experience would be required. Tr.
932:17-25.
Although under Plaintiff’s definition a POSA would have a bit more practical
experience, the differences between the two definitions appears to be immaterial. Both
experts agree that their opinions would not change if the Court adopted the other’s
definition of a POSA. Tr. 554:6-555:1; Tr. 933:11-13. Consequently, as resolution of the
50
differences between the parties’ definitions will not affect the outcome of the case, the
Court need not resolve them.
4. Gabapentin Patents
Depomed’s asserted composition and method claims are directed to a specific type
of extended-release gabapentin oral dosage form that releases gabapentin in the stomach
over several hours and delivers the drug in such a way that the human achieves certain
blood concentrations of the drug and that the gabapentin has a therapeutic effect. JTX 3- 7.
a. Obviousness Contentions
Actavis contends as follows:
• The asserted claims of the ‘927 Patent would have been obvious to one of ordinary
skill over Depomed’s WO ‘107 (DTX 234) in view of Rowbotham (DTX 313), along with
the knowledge of a person of ordinary skill in the art as evidenced McLean (DTX 267) and
Stevenson (PTX 500).
• The asserted claim of the ‘989 Patent would have been obvious to one of ordinary
skill over WO ‘107 (DTX 234) in view of Rowbotham (DTX 313), along with the
knowledge of a person of ordinary skill in the art as evidenced by McLean (DTX 267) and
Stevenson (PTX 500).
• The asserted claims of the ‘756 Patent would have been obvious to one of ordinary
skill over Depomed’s WO ‘107 (DTX 234) in view of Rowbotham (DTX 313), along with
the knowledge of a person of ordinary skill in the art as evidenced by McLean (DTX 267)
and Stevenson (PTX 500).
51
• The asserted claims of the ‘332 Patent and the ‘992 Patent would have been
obvious to one of ordinary skill over WO ‘107 (DTX 234) or WO ‘128 (DTX 236) in view
of Rowbotham (DTX 313).
b. Priority Dates
There appears to be no dispute as to the relevant dates with respect to the
obviousness analysis. The priority date of the Gabapentin Patents (‘927, ‘989, ‘756, ‘332
and ‘992 Patents) is October 25, 2001. See JTX003 (‘927 Patent) (issued from application
no. 10/280,309); JTX004 (‘989 Patent) “Related U.S. Application Data” (issued from
continuation of application no. 10/280, 309 and claiming priority to provisional application
no. 60/335,248 filed October 25, 2001); JTX005 (‘756 Patent), “Related U.S. Application
Data” (claiming priority to provisional application no. 60/335,248 filed October 25, 2001);
JTX006 (‘332 Patent), “Related U.S. Application Data” (same); JTX007 (‘992 Patent),
“Related U.S. Application Data” (same).
c. Prior Art
(i) Gabapentin
Gabapentin was conceived of and synthesized in the early 1970s by Goedecke,
A.G., in Germany, which was part of Warner-Lambert at the time. Stip. Facts ¶ 117; Tr.
857:3-9. In December 1993, the FDA approved and Warner-Lambert commercialized an
immediate release formulation of gabapentin. Stip. Facts ¶ 119; Tr. 686:1-5. Neurontin is
the trade name of this immediate release formulation, and its recommended dosing schedule
is three times per day. Tr. 731:19-20; 751:3-5.
When Neurontin was first approved in the United States, it was indicated “as
adjunctive therapy in the treatment of partial seizures with and without secondary
52
generalization in patients over 12 years of age with epilepsy. Neurontin is also indicated as
adjunctive therapy in the treatment of partial seizures in pediatric patients age 3 - 12 years.”
DTX 291 at GRALISE_JDG_00000158.
In the 1990’s the use of gabapentin grew beyond the treatment of epilepsy and was
prescribed off label for other purposes. Tr. 672:22-24. The Rowbotham reference,
published in 1998, concluded that Neurontin was effective for the treatment of neuropathic
pain, such as postherpetic neuralgia. DTX 313 (Michael Rowbotham et al., Gabapentin for
the treatment of Postherpetic Neuralgia: A Randomized Controlled Trial, 280 J. AM. MED.
ASS’N 1837, 1837-42 (1998); Tr. 559:4-560:5; 857:3-8. As a result of its off label uses,
Neurontin eventually became a blockbuster drug product by the late 1990s. Tr. 772:6-11;
975:25 – 976:4; 1067:24 – 1068:14.
Gabapentin has a number of properties that would need to be considered with
respect to the development of a controlled-release formulation:
• Absorption
The evidence shows that a POSA in the late 1990’s/early 2000 seeking to create an
extended-release gabapentin formulation would have had to account for several unique
characteristics of the drug. The first was to ensure that the drug was available for
absorption. Tr. 964:10-25. Gabapentin was known in the prior art to have some unique
absorption properties that would impact the development in a controlled-release
formulation. Gabapentin was known to be highly water soluble. Tr. 558:5-559:3; DTX
267 at GRALISE_JDG_ 00000126; Tr. 703:19-24; DTX 291 at GRALISE_JDG_
00000152; Tr. 263:16-17. It was also known to have a narrow window of absorption in the
upper gastrointestinal tract (that is, it is absorbed only in the upper region of the small
53
intestinal tract) and to be absorbed via a saturable transporter. Tr. 560:6-561:9, 564:22565:1; PTX 500 at GRALISE_JDG_ 00000601, GRALISE_JDG_00000603; DTX 267;
711:18-22 (testimony that McLean states that gabapentin “is transported across the gut wall
by the L system amino acid transporter,” and that the “[a]bsolute bioavailability of
gabapentin is dose-dependent, probably as a result of the saturable absorption by the L
system amino acid transporter.”). Thus, to develop a controlled release formulation, a
POSA would have needed to account for gabapentin’s unique absorption properties
formulation. According to Plaintiff, gabapentin’s absorption properties created substantial
challenges to the development of a controlled-release formulation. Tr. 964:2-8. Defendant,
on the other hand, contends that a POSA would have known that these properties made
gabapentin ideal for a gastric-retained controlled-release dosage form. Tr. 637:2-6; 964:15965:16; see DTX 234.
There is no dispute that gabapentin has a narrow window of absorption. Tr. 560:68; 983:12-17; 828:16 – 829:5. Defendant’s expert Dr. Flanagan testified that the window of
absorption was an important characteristic for a formulator developing a controlled-release
dosage form. Dr. Flanagan testified that “[i]f the drug is only absorbed in a certain region
of the GI tract, then one has to develop a formulation that will release it in the region where
it will be absorbed.” Tr. 564:13-17; see also Tr. 964:15-17 (Dr. Felton: “[B]ecause the
drug is absorbed in the upper regions of the small intestine, the drug would need to be
released at that site in order to be absorbed into the body.”)
Pre-clinical studies in dogs by Stevenson show that gabapentin absorption takes
place in the small intestines but largely does not occur in the large intestines. Tr. 339:1116; PTX 500 at Gralise_JDG_00000602. Stevenson states “[c]omparison of the blood-level
54
data from oral and jejunal administration of gabapentin indicates that there is substantial
absorption from the duodenum and upper jejunum. Most important, gabapentin plasma
levels from colonic administration are substantially lower than those obtained from oral and
upper intestinal administration.” Tr. 339:17 – 340:2; PTX000500 at
Gralise_JDG_00000602.
The poor absorption of gabapentin and its restricted area of absorption posed certain
challenges to designing an effective controlled-release formulation. As noted by one
reference in 2000:
Gabapentin has a half-life of 5 to 7 hours and requires an administration
interval of 8 hours; however, it is absorbed by an L- amino acid carrier
system that may not be present throughout the gastrointestinal tract and
which may be saturable. These characteristics would limit the use of an ER
formulation.
PTX 501; Collins et al. (2000) at 205 (citation omitted).); see also Tr. 853:8-16.
Similarly, other literature noted:
To date, efforts to develop a sustained release formulation of gabapentin
have failed, primarily due to the lack of significant absorption of the drug in
the large intestine (Kriel et al., 1997).
Cundy et al. (2004) PTX000269 at 316.
With gabapentin being absorbed in the upper regions of the gastrointestinal tract, the
drug would need to be released at that site or above in order to be absorbed into the body.
Plaintiff’s expert Dr. Felton stated that, as a result, “[t]here are potentially two general
approaches to achieve that drug release in the right location in the body. The first would
have been to slow intestinal motility of the dosage form in the small intestines.” Tr.
964:18-25. However, that would require additional medication to achieve and Dr. Felton
opined that “it is probably not a good idea to have to take one medication in order to get a
55
second medication absorbed.” Tr. 964:24-25. The second alternative was to deliver the
drug by way of one of the several available gastro-retentive systems. Tr. 964:10 – 965:17,
967:21 – 969:8. See also PTX 274 (Davis 2005) (“Methods designed to provide longer
contact of the drug or delivery system with the crucial absorption region fall into two
different categories: (i) those that attempt to slow down transit through the small intestine;
and (ii) those that attempt to hold the drug formulation above the absorption window
through gastric retention.”)
• Pharmacokinetics and Bioavailability
As noted above, gabapentin is absorbed in the upper gastrointestinal tract by
saturable transporters. Tr. 748:20 – 749:3; 563:8-16. It was reported for the first time in
1995 that gabapentin was saturably absorbed by L-amino acid type transporters. Tr. 747:9
– 748:7; PTX000271. Thus, a second challenge faced in developing an extended-release
formulation of gabapentin would have been pharmacokinetics and bioavailability, that is,
ensuring that the drug release occurs at a rate that will be not saturate the saturable
absorption system but yet is high enough to get therapeutically meaningful blood levels.
Tr. 563:8-16. “Saturable absorption” means that the transporters can only bring in a certain
amount of drug at any given time. Tr. 563:19- 24; Tr. 710:11-17. Consequently, if more
than that amount of drug reaches the transporter, then the additional amount of drug simply
will not be absorbed. Tr. 563:19-24; 710:11-17.
Gabapentin’s short half life also was potentially problematic to the development of
an extended-release formulation. Gabapentin’s half-life of about 6 hours meant that if a
single dose per day was administered, absorption would need to be maintained over an
56
extended period of time as the half-life in the blood would be short. Effectively, after 10-12
hours with no absorption, 75% of gabapentin would be eliminated. Tr. 759:4-7, 758:7-13.
• Degradation
Another challenge facing a POSA seeking to develop an extended-release
gabapentin dosage form is that in the acidic environment of the stomach gabapentin
degrades into lactam, which can be toxic. Tr. 855:7-13. Gabapentin degrades slowly into
lactam as a function of pH, temperature and buffers which can accelerate some of this
process. Tr. 856:1-3; PTX000290. As in the case of any drug that degrades in an acidic
environment such as in the stomach, as the drug degrades there will be less drug that could
be absorbed for its therapeutic effect.
Defendant takes the position that degradation into lactam is a challenge that has
already been overcome. On cross examination, Plaintiff’s expert Dr. Gidal admitted that
Warner-Lambert had previously discovered “that gabapentin can convert into lactam,” and
that Warner-Lambert “solved the problem and got a patent on that solution.” Tr. 858:1218. However, Defendant failed to offer to any further evidence as to what that “solution”
is, under what circumstances it is employed, and whether and to what extent it may apply in
the context of the development of an extended release gabapentin formulation. The Court,
therefore, cannot conclude that the existence of this “solution” negates from consideration
by a POSA the challenge of avoiding the degradation of gabapentin into lactam in the
development of a controlled-release gabapentin formulation.
• Blockage
In addition to lactam formation, evidence shows that another safety challenge with a
gastro-rententive system is avoidance of potential blockages. Because such a formulation is
57
designed to stay in the stomach for an extended period, a formulator must consider the risk
the dosage form can get lodged in the digestive tract. Tr. 966:12-19. For example, the
2005 Davis reference notes that the gastric retentive system must be retained in a safe and
reliable manner: “It must not swell or expand in the esophagus or in the intestines, if it
emptied prematurely from the stomach (e.g. problems could arise from the formation of an
insoluble mass known as bezoar).” PTX274 at DEPOACT0970226.
• Therapeutic Effectiveness
Yet another consideration is ensuring that a therapeutically effective amount of the
drug gets to the target site in order to exert its therapeutic effect. Tr. 966:20 – 967:1.
Therapeutically effective dosages for gabapentin in an immediate release
formulation (Neurontin) were known in the prior art. Daily doses ranging from 300 mg/day
to 3,600 mg/day of gabapentin were known to be an effective treatment of neuropathic pain.
Tr. 559:4-560:5; Tr. 619:11-14, 622:17-623:3; DTX 313 at GRALISE_JDG_00000452
(Study participants “began with an initial dose of 300 mg/d” which was then “increased
over the next four weeks (titration period) in a step-up manner (900, 1800, 2400, and 3600
mg/d divided three times a day), to a maximum total dose of 3600 mg/d.”),
GRALISE_JDG_00000451 (“Conclusions—Gabapentin is effective in the treatment of pain
and sleep interference associated with [postherpetic neuralgia].”).)
With respect to the treatment of epilepsy, the Neurontin label states that an
effective dose of Neurontin® is 900 to 1800 mg/day and given in divided
doses (three times a day) using 300 or 400 mg capsules, or 600 or 800 mg
tablets. The starting dose is 300 mg three times a day. If necessary, the dose
may be increased using 300 or 400 mg capsules, or 600 or 800 mg tablets
three times a day up to 1800 mg/day. Dosages up to 2400 mg/day have been
well tolerated in long-term clinical studies. Doses of 3600 mg/day have also
58
been administered to a small number of patients for a relatively short
duration, and have been well tolerated.
Tr. 620:15-24; DTX 291 at GRALISE_JDG_00000169.
However, as Dr. Gidal testified, information about the therapeutic efficacy of the
immediate-release formulation Neurontin does not necessarily translate to an extended
release formulation. Tr. 842:21-843:15. According to Dr. Gidal, this is due to the saturable
absorption seen with gabapentin, which is more unpredictable than linear absorption, as
well the inter-person variability and even the effect of food on the absorption of gabapentin.
Tr. 817:8-818:1.
(ii) Gastric Retained Dosage Forms Generally
According to Defendant’s expert Dr. Flanagan, there were no FDA approved gastric
retained dosage forms available in the market in 2001. Tr. 663:8-12. In fact, the weight of
the credible evidence shows that in the late 1990’s and early 2000’s, the gastro-retentive
drug delivery system was an emerging art and was not well-developed. Tr. 968:15-21.
The Hwang reference provides a comprehensive view of the state of the art as of
1998. See DTX 22, Sung-Joo Hwang, et al., Gastric Retentive Drug-Delivery Systems,
Critical Reviews, 15 CRITICAL REVIEWS IN THERAPEUTIC DRUG CARRIER SYS.
243, 243–84 (1998). In 1998, no long-term gastric retention device was available, and a
need for such a device was expressed in the Hwang paper. Tr. DTX 222; Tr. 948:3-17.
The Hwang reference describes several possible approaches to gastro-retentive drug
delivery system, Tr. 656:9-11, which include: (1) gas generating floating systems; (2) low
density core systems; (3) high density systems; (4) mucoadhesive systems; (5) magnetic
systems; (6) unfoldable, extendible or expandable systems, including systems extending to
59
complex geometric shapes and larger sizes; and (7) superporous hydrogel systems. DTX
222, GRALISE_JDG_00000396-415; Tr. 661:13-662:9.
Hwang concludes that it is unclear at that time whether any gastric retention device
is “truly working or not” and “[w]e have great hope that a long-term gastric retention
device for human application will be developed in the near future.” DTX 222,
GRALISE_JDG_ 00000417, GRALISE_JDG_00000418; Tr. 948:3-17. The concluding
section of this reference, under the heading of “Optimization of Gastric Retention Devices
for Human Applications”, states:
The literature is full of conflicting information. Gastric retention devices that
work in one laboratory often prove not to work in others. When a proposed
gastric retention device doe[s] not work, the immediate conclusion drawn by
the study is obviously that the system does not work. As we reviewed the
literature, we have noticed a few things. First of all, no study has been done
comprehensively to conclude whether any gastric retention device is truly
working or not. Most of the studies that showed that a proposed system did
not work were often based on inadequate controls and an inadequate number
of volunteers. While the studies may have produced negative results, these
results were hardly sufficient to conclude that the system did not work.
*
*
*
“The lesson here is that there's too much variation in human volunteers,
unrealistic to derive any conclusion from advanced retention study involving
only a handful of human volunteers.”
*
*
*
We have great hope that a long-term gastric retention device for human
application will be developed in the near future. As presented here, each
gastric retention system approach has its own unique concept and each
requires further improvements to be effective. Progress will only be possible
if all the researchers in the field work together to analyze a concept, test it,
and find ways to overcome limitations. Only after we accomplish long-term
gastric retention devices can the full benefits of controlled-release
technologies be realized for oral controlled-release dosage forms.
DTX 222 at GRALISE_JDG_0000417-18.
60
(iii) International Patent Publication No. WO 98/55107
International Patent Publication No. WO 98/55107 A1 (“WO ‘107”), which was
authored by Depomed employees and published December 10, 1998, is titled “GastricRetentive Oral Drug Dosage Forms for Controlled Release of Highly Soluble Drugs.” DTX
234 at GRALISE_JDG_00000841. The abstract for WO ‘107 states that the purpose of the
described dosage form is as follows:
Drugs that are freely or highly soluble in water are formulated as unit dosage
forms by incorporating them into polymeric matrices comprised of high
molecular weight hydrophilic polymers that swell upon imbibition of water.
The dosage form can be a single compressed tablet[]. . . . The oral
formulation is designed for gastric retention and controlled delivery of an
incorporated drug into the gastric cavity, and thus administered, the drug is
released from the matrix into the gastric fluid by solution diffusion. The
swollen polymeric matrix, having achieved sufficient size, remains in the
gastric cavity for several hours if administered while the patient is in the fed
mode, and remains intact long enough for substantially all of the drug to be
released before substantial erosion of the matrix occurs . . . .
Tr. 556:22-557:8; DTX 234 at GRALISE_JDG_00000841.
As described by Dr. Flanagan, the WO ‘107 discloses
a drug being dispersed in a polymeric matrix and that matrix is water
swellable. The drug is released based on diffusion that can be slowed by
altering formulation characteristics. The polymers in the matrix swell upon
ingestion and that promotes gastric retention during the fed mode. The
swelling is also in a dimensionally-unrestricted manner and soluble drugs
can be absorbed -- they're absorbed mostly in the stomach or high in the
gastrointestinal tract -- such as Metformin can be incorporated into the
formulations that are disclosed and that the said dosage form comprises a
solid polymeric matrix in which the drug is dispersed.
Tr. 556:20 - 557:8.
In particular, WO ‘107 discusses gastro-retentive systems “to treat local conditions
in the stomach as well as to provide control release for drugs that are absorbed from a
narrow window of absorption.” Tr. 973:8-974:3. In vitro release examples that are cited in
61
WO ‘107 are Metformin hydrochloride, Captopril and Vancomycin.” Tr. 973:22-24.
Gabapentin is not expressly cited as a possible drug to be used in WO ‘107 dosage form.
(iv) International Patent Publication No. WO 99/47128
International Patent Publication No. WO 99/47128 A1 (“WO ‘128”), entitled
Biphasic Controlled Release Delivery System for High Solubility Pharmaceuticals and
Method, was published on September 23, 1999. DTX 236 at GRALISE_JDG_00000055.
Dr. Mayersohn explained that WO ‘128 is directed to “a new dosage form for highly water
soluble medicaments, such as the antidiabetic metformin, which provides for extended
release of the drug and prolonged gastric residence which enables efficient delivery of
drugs normally absorbed in the upper gastrointestinal tract, and to a method for preparing
such dosage form.” Tr. 698:8-14; DTX 236 at GRALISE_JDG_00000057. The WO ‘128
application deals with one specific drug, Metformin, Tr. 698:17-18, but lists a number of
“high water soluable drugs” and types of “water-soluable drugs” that can be included in the
described formulations. GRALISE_JDG_00000079-82. It does not disclose gabapentin or
a dosage form containing gabapentin. Tr. 726:1-3; 975:16-24; 1038:24-25.
(v) Rowbotham
In December of 1998, an article by Michael Rowbotham was published in the
Journal of the Medical Association entitled Gabapentin For the Treatment of Postherpetic
Neuralgia. Rowbotham et al., Gabapentin for the treatment of Postherpetic Neuralgia: A
Randomized Controlled Trial, 280 J. AM. MED. ASS’N 1837, 1837-42 (1998).
Rowbotham concluded that gabapentin was an effective treatment of neuropathic pain, with
daily doses ranging from 300 mg/day to 3,600 mg/day. Tr. 559:4-560:5; DTX 313 at
GRALISE_JDG_00000452 (Study participants “began with an initial dose of 300 mg/d”
62
which was then “increased over the next four weeks (titration period) in a step-up manner
(900, 1800, 2400, and 3600 mg/d divided three times a day), to a maximum total dose of
3600 mg/d.”), GRALISE_JDG_ 00000451 (“Conclusions—Gabapentin is effective in the
treatment of pain and sleep interference associated with [postherpetic neuralgia].”).) This
reference discusses immediate release gabapentin only.
(vi) Comparison of the Inventions and Prior Art
Defendant presented expert testimony explaining that the prior art as discloses or
suggests most of the limitations of the asserted claims. Much of this testimony is
undisputed, thus, as Defendant’s counsel indicated in his opening statement, the key issues
to be decided as related to obviousness center on motivation to combine the prior art
references and whether there would have been a reasonable likelihood of success in doing
so. The Court sets forth below, however, certain limitations from the asserted claims not
disclosed in the prior art:
• No reference discloses gabapentin from an extended-release dosage form with
bioavailability that is at least 80% as that from an immediate release dosage form. All
asserted claims of the ‘989, ‘756, ‘332 and ‘992 Patents require bioavailability at least 80%
as that from an immediate release form. Claim 10 of the ‘989 Patent, claims 1, 2, 5-7, 11 of
the ‘756 Patent, claims 1, 6, 17, 22, 24 of the ‘332 Patent and claims 1, 5, 22 of the ‘992
Patent are asserted in this case. None references relied upon disclose this limitation. Tr.
1031:3-10; Tr. 576:8-13; 997:13 – 998:4; 1038:24 – 1039:3.
• No reference teaches gabapentin from an extended-release dosage form with lower
Cmax than that from an immediate release dosage form. Asserted claims 1, 2, 5-7, 11 of
the ‘756 Patent, 1, 6, 17 of the ‘332 Patent and 1, 5 of the ‘992 Patent require that the
63
controlled-release gabapentin dosage form achieve in vivo a lower Cmax than the
immediate release gabapentin dosage form. The WO‘107 reference does not specifically
state that its formulation achieved lower Cmax of any drug compared to that from an
immediate release dosage form. Tr. 1037:8-17; 614:19-21.
• No reference teaches gabapentin from an extended-release dosage form with
longer Tmax than that from an immediate release dosage form. The WO ‘107 reference
does not specifically state that its formulation achieved longer Tmax of a drug compared to
that from an immediate release dosage form. Tr. 1038:1-8. The WO ‘128 reference does
not specifically state that its formulation would result in gabapentin with longer Tmax
compared to that from an immediate release dosage form. Tr. 1038:24 – 1039:3. Other
references relied upon also does not teach pharmacokinetic parameters from a gastric
retained dosage form or from a gabapentin dosage form. Tr. 998:5-22.
• No reference teaches that “at least 40 wt% of the gabapentin is retained in the
dosage form one hour after administration.” Asserted claims 18, 25, 26, 34, 61, 62 of the
‘927 Patent, claim 10 of the ‘989 Patent and claims 1, 2, 5-7, 11 of the ‘756 Patent contain
this limitation. The WO ‘107 reference does not refer to gabapentin, and has no in vivo
data to show that one hour after administration gabapentin is retained at least 40% wt after
administration. Tr. 994:21 – 995:10; 996-22 – 997:12.
• No reference teach “the dosage form provides administration of at least 85 wt% of
the gabapentin to be delivered over a period of about 5-12 hours.” Claim 26 of the ‘927
Patent requires that the controlled-release gabapentin dosage from that 85% be delivered
over a period of about 5-12 hours. It is undisputed that there is no in vivo data presented in
the WO ‘107 reference. Tr. 996:6-21.
64
c. Motivation
(i) Motivation - Generally
As Actavis argues, evidence at trial showed that one of ordinary skill in the art in
2001 would have had a general motivation to make a controlled release gabapentin
formulation to alleviate the burden on patients to take multiple doses per day, improve
patient compliance, and reduce the incidence of side effects. Tr. 751:11-18 (Bockbrader:
reduce frequency, improve compliance); Tr. 963:21-964:1 (Felton: reduce frequency,
improve compliance, lessen side effects ) Tr. 558:5-559:3 (Flanagan: reduce frequency,
improve compliance); Tr. 873:12-22 (Brown: experiences compliance issues with thrice
daily dosing); DTX 267 at GRALISE_JDG_ 00000130 (short half life and resulting threetimes per day dosing may result in compliance problems).
However, despite the potential advantages identified with respect to a controlledrelease gabapentin formulation, Depomed argues that “no specific motivation existed to
make an effective extended-release gabapentin dosage form” because of the challenges that
existed to creating such a dosage form. The Court agrees that there is evidence of
challenges that may have dissuaded a POSA from believing an effective controlled release
formulation of gabapentin could be developed. First, Depomed points to a study by Dr.
Gidal published in 1998 that concluded that slower delivery of gabapentin to overcome its
saturation problem did not work at a lower dose as the researchers had anticipated. See
PTX 502 at 91-92 (Gidal et al, Gabapentin Bioavailability: Effect of Dose and Frequency
of Administration in Adult Patients With Epilepsy, EPILEPSY RESEARCH 31 (1998)).
With a drug like gabapentin that is saturable, there would ostensibly be a motivation
to create a controlled-release dosage form because such a dosage form would not deliver
65
the entire dose immediately but rather over a period of time, therefore lessening the
problem of saturation. Tr. 364:10-15; 1010:8-12. Gabapentin being absorbed by a
saturable mechanism, Dr. Gidal and his team hypothesized that if they gave the same daily
dose of the drug but administered it more frequently to simulate a slowly releasing
controlled-release dosage form, the bioavailability of drug would improve and more of the
drug would get absorbed. Tr. 819:15 – 820:6. However, Dr. Gidal’s studies showed,
unexpectedly, that although bioavailability improved with patients who were given a 4800
mg/day dose of gabapentin, it did not with a 3600 mg/day dose of gabapentin. Tr. 820:7 –
822:10. Thus, Depomed contends that a POSA would have been skeptical that an
extended-release dosage form could avoid saturation.
Second, Depomed points to the fact that the stomach environment was thought to
accelerate the degradation of gabapentin into lactam. According to Hwang, “drugs unstable
in the acidic pH of the stomach cannot be used in gastric retentive devices.” DTX 222 at
GRALISE_JDG_ 00000387. As noted earlier, “[g]abapentin is a drug that was known to
degrade in the presence of acid more quickly to a toxic lactam.” Tr. 971:22 – 972:19. Dr.
Felton testified that based on this that a POSA would conclude that, as a result, it would
“not be a good idea” to put gabapentin in a gastric retained delivery system. Tr. 972:20 –
973:3. Dr. Felton further explained that there were other references also demonstrating
“that the drug does degrade to a lactam, a toxic component, and the rate at which that
degradation happens is going to be dependent on what people have consumed or what’s is
in their stomach, whether there’s buffer, what the pH is.” Tr. 998:24 – 1001:3.
In response to the express concerns about degradation, Actavis refers to
International Patent Publication No. WO 93/18755 (“WO ‘755), entitled Aykly-Substituted
66
Cellulose-Based Sustained-Release Oral Dosage Forms that was published in 1993. This
reference states that its disclosed dosage forms can protect acid- labile peptides, proteins, or
proton pump inhibitors from gastric fluid. DTX 230 at GRALISE_JDG_00000902 –
GRALISE_JDG_ 00000903. The WO ‘755 reference teaches drug/polymer mixtures in the
form of a “plurality of particles” that are delivered to the stomach in a “tablet or capsule
[which] rapidly disintegrates in the gastric fluid to permit the particles to disperse in the
stomach. DTX 230 at GRALISE_JDG_ 00000900 and GRALISE_JDG_00000905. There
is no evidence, however, that a person of ordinary skill in the art would look to WO ‘755
for teaching on how to protect gabapentin from the acidic environment of the stomach
because this reference contemplates very different release-controlling mechanisms as
compared to the Gabapentin Patents. In contrast to the inventions of the Gabapentin
Patents, which require the use of the highly soluble drug gabapentin, WO ‘755 is directed to
the formulation of dosage forms for drugs with “limited solubility.” DTX 230 at
GRALISE_JDG_00000901. Further, the release of these low solubility drugs from a matrix
is controlled by their rate of dissolution, while the Gabapentin Patents release drug
primarily by diffusion. DTX 230 at GRALISE_JDG_ 00000905; JTX003 12:48-49; see
also Tr. 264:8 – 265:19.
Also supporting Depomed’s argument that no specific motivation existed to make
an extended-release gabapentin dosage form is a concern that would have existed as to a
dosage form that is dependent on food, because food has a variable effect on gabapentin
absorption. Studies have indicated that food has a variable effect on gabapentin absorption.
In one study, it was hypothesized that, in the presence of a protein rich diet, gabapentin
absorption would be reduced because the amino acids in the protein would compete with
67
gabapentin for transport since both gabapentin and certain amino acids are transported by
the same transporter, i.e., “System L.” Tr. 829:21-831:8. Contrary to expectations, the
study showed that the presence of a protein rich diet enhanced the bioavailability of
gabapentin. Tr. 831:8-24; PTX 276 at DEPOACT0970241 (Gidal et al., Effect of a HighProtein Meal on Gabapentin Pharmacokinetics, 23 EPILEPSY RESEARCH 71, 74 (1996))
In another study, Dr. Gidal evaluated gabapentin absorption following a diet of
Neurontin mixed with water, apple sauce, orange juice or chocolate pudding. Tr. 832:18 –
834:8; PTX000270 at DEPOACT0958992 (Gidal et al., Gabapentin Absorption: Effect of
Mixing with Foods of Varying Macronutrient Composition, 32 THE ANNALS OF
PHARMACOTHERAPY
405 (1998). The data from this study suggested that food composition,
particularly protein, could influence gabapentin absorption.
Dr. Gidal testified that he would have been skeptical of the ability to create an
effective controlled-release dosage form of gabapentin because of, among other things, the
effect of food on absorption. Tr. 834:19 – 835:20. Dr. Felton similarly noted that the
variable effect of food on absorption was a factor that would lead a POSA to believe that
gabapentin would not be suitable for use in a gastric-retained dosage form dependent on the
presence of food in the stomach. 967:4-10.
In a book chapter that reflect his opinions in 2000-2001, Tr. 738:5-14, 738:25 –
740:11, Actavis expert Dr. Mayersohn discussed the then-state of the art thinking about
how food impacts drug absorption. Tr. 737:7-15, 738:5 – 740:11. He wrote the following
in regard to food effects on drug absorption:
Several recent publications have reviewed the effects of food on drug
absorption in humans [70-72]. The effect of food on the gastrointestinal
absorption of drugs is complex and multidimensional. We are only now
68
beginning to understand this complexity. The physical presence of food in
the GIT may play a significant role-in affecting the efficient absorption of a
drug from an oral dosage form. The ultimate effect of food on the rate and/or
extent of gastrointestinal absorption is a function of numerous interacting
variables. While some general rules may be postulated, the effect of food on
a given drug and its dosage form will require, in general, individual
investigation. The U.S. Food and Drug Administration (FDA) has
recognized this complexity and requires that all dosage forms that do not
immediately release drug (e.g., controlled-release formulations) undergo a
food-effects study in humans, for which a “Guidance” has been written
(these are available on the FDA webpage-fda.gov).
PTX000521 at DEPOACT0982013; Tr. 738:15 – 739:22. He further noted that there were
variables that a POSA must consider with respect to how food effects absorption including
“physical chemical characteristics of the drug (e.g., aqueous solubility, oil/water partition
coefficient, and stability in gut fluids), the dose of drug, the characteristics of the dosage
form, time of drug administration relative to food ingestion, amount of food, and type of
food.” PTX 521 at DEPOACT0982013; Tr. 739:23 – 740:11
In response to evidence and argument regarding absorption variability based upon
food, Actavis provides little more in the way of evidence than the Neurontin label,
awareness of which was acknowledged by Depomed’s witnesses on cross examination,
which states that Neurontin can be taken with or without food. DTX 291 at
GRALISE_JDG_00000169. Defendant’s implication is that absorption variability based
upon food is clinically insignificant. While this is reasonable to infer with respect to the
immediate release formulation of gabapentin, there has been no credible evidence presented
to indicate the same would be true for an extended-release formulation that releases the
drug in incremental amounts over a period of time. The dosage forms of WO ‘107 and WO
‘128, for example, must be taken with food, and it is possible that a POSA would try to
minimize the food effect by looking for a dosage form that was not dependent on food.
69
(ii) Motivation - WO ‘107
As already stated, by October 2001, it was known in the art that gabapentin is highly
water soluble and absorbed high in the gastrointestinal tract through a saturable carriermediated system. Tr. 686:1-5, 702:4-7; 845:24; 963:2-6; DTX 267 at GRALISE_JDG_
00000126-28. Given these properties of the drug, a POSA would know that a conventional
controlled release dosage form that releases drug along the entire length of the
gastrointestinal tract would be inappropriate for gabapentin. Tr. 637:2-6, 702:4-16, 713:22714:17, 769:24-770:3. Instead, as Dr. Felton explained, a gastric retentive system was the
better of the potential approaches to make a controlled release form of gabapentin because
it would keep the gabapentin in a place above its window of absorption for an extended
period of time. Tr. 964:15-965:16. Named inventor, Dr. Hou, confirmed that it was these
known absorption characteristics that made gabapentin a good candidate for a gastric
retained, controlled-release dosage form. Tr. 548:11-14. Dr. Hou stated that non-gastric
retained dosage forms were not considered for gabapentin. Tr. 548:15-17.
The WO ‘107 describes a gastric retained dosage form. As stated in the Summary of
the Invention in WO ‘107:
The invention . . . provides enhanced absorption of soluble drugs that are
absorbed mostly in the stomach or high in the gastrointestinal tract, such as
metformin hydrochloride or ciprofloxacin. The invention is also useful in
providing a multi-hour flow of a drug past the upper part of the small
intestine (the most efficient absorption site for many agents).
DTX 234 at GRALISE_JDG_00000845. Dr. Flanagan stated that one of ordinary skill in
the art would consider WO ‘107 dosage form a suitable one for gabapentin because
gabapentin is similarly absorbed primarily high in the gastrointestinal tract and is water
soluble. Tr. 557:9-25. Dr. Flanagan also opined that one of ordinary skill in the art would
70
also have had a motivation to replace metformin in the gastric retained formulations
disclosed in Depomed’s WO ‘107 with gabapentin because both drugs were known to
exhibit saturable absorption high in the gastrointestinal tract. Tr. 564:22-565:1.
However, the evidence shows that there are a number of reasons that a POSA would
not necessarily be motivated to combine WO ‘107 with the identified references to produce
the inventions recited in the asserted claims of the Gabapentin Patents. First, as Depomed
notes, each asserted claims of the Gabapentin Patents either expressly recites one or more
pharmacokinetic parameter (such as AUC, Cmax or Tmax) or it recites therapeutically
effective gabapentin (or sometime both). JTX003, JTX004, JTX005, JTX006, JTX007.
The WO ‘107 reference does not disclose any pharmacokinetic element of gabapentin or
any drug or any therapeutic administration of a drug. Tr. 974:4-15; 842:7-17; 656:1-3.
Without such data, there is insufficient information to know that gabapentin would in fact
be absorbed into the blood stream with the appropriate kinetics such that its bioavailability
will be at least 80% as that of an immediate release dosage form or with lower Cmax or
longer Tmax and, as such, a POSA would be less inclined to use gabapentin in the WO
‘107 dosage form. Tr. 1031:17 – 1032:5; 1037:19- 25; 1038:9-17.
In this regard, Depomed also points to the fact that WO ‘107 provides in vitro
dissolution curves for drugs like vancomycin which were known to be poorly absorbed
orally and would be a poor candidate for therapeutically effective dosage form. Tr.
1015:14- 24; 1059:4-13. Consequently, a POSA would understand that the WO ‘107
reference teaches a dosage form and not that the drug used in the WO ‘107 dosage form
would necessarily be absorbed into the blood to result in certain pharmacokinetic
parameters or that the drug would be therapeutically effective. Tr. 1059:17-23.
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Depomed also argues that a “having a general goal of at least 80% AUC, lower
Cmax and higher Tmax of gabapentin from a controlled-release versus immediate-release
dosage form is insufficient clear motivation to combine when none of the references teach
that gabapentin from a controlled-release dosage would be absorbed in blood.” D.I. 361 at
135. Defendant’s expert Dr. Flanagan testified that all controlled-release formulations are
designed to meet the claim limitations of without loss in bioavailability (AUC) or lower
Cmax. Tr. 608:14 – 609:10. Dr. Flanagan further testified that without loss in AUC and
lower Cmax are the natural consequences of controlled-release dosages. Tr. 609:14 –
610:1. Depomed’s expert Dr. Derendorf, however, disagreed with Dr. Flanagan. (Notably,
Dr. Derendorf is an expert in pharmacokinetics; Dr. Flanagan is not.) Dr. Derendorf
explained that controlled-release formulations can be of many types with different targets,
typically the relevant pharmacokinetic profile being one that would be therapeutically
effective. According to Dr. Derendorf, such a profile may have a lower Cmax, but that is
not always true. Tr. 1032:21 – 1033:9. If the controlled-release product is below minimum
effective concentration, the controlled-release product even though it meets all the
pharmacokinetic goals, nonetheless would be therapeutically ineffective. Tr. 1034:22 –
1035:18. According to Dr. Derendorf, the minimum effective concentration for gabapentin
is not known; therefore, simply by looking at a dose concentration profile, one would not
know whether the drug is therapeutically effective or not. Tr. 1035:5-18. The Court finds
Dr. Derendorf’s testimony persuasive.
Next Depomed argues that no specific motivation existed to put gabapentin in the
WO ‘107 dosage form. Dr. Felton testified a POSA in October 2001 would not select
gabapentin for use in the dosage form disclosed in WO ‘107 because:
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- Gabapentin is not mentioned in the WO ‘107 reference; Tr. 987-988;
- Gabapentin was known to be sensitive to degradation in acidic pH and the dosage
form is designed to reside in the stomach for several hours, id.;
- The WO ‘107 reference “focuses quite a bit on a treatment for local effect in the
stomach” and gabapentin is not used for such purpose id.;
- Gabapentin’s “absorption is influenced by the presence of food and the ‘107 patent
application requires the drug product to be administered with food”, id.;
- One of skill in the art would also not choose gabapentin based on the disclosure of
metformin in the WO ‘107 reference—according to Dr. Felton they are distinct chemical
entities with different chemical properties and cannot simply be substituted, id.;
- One skilled in the art would not try to develop an extended- release dosage of
gabapentin without knowing if release rate of the drug from the dosage form was
appropriate. As stated by Dr. Felton, “Without understanding the saturable kinetics, one of
skill in the art would not know how quickly the drug needs to come out of that system or
for that matter, what blood levels are necessary to achieve a therapeutic effect.” Tr. 987992.
Significantly, gabapentin was not identified in WO ‘107 reference as a potential
drug to use in the ‘107 dosage form, even though well-known Neurontin was a billion
dollar a year drug. Tr. 672:22-673:9. Further, the WO ‘107 reference states that the
formulation is designed for gastric retention, but there is no evidence that the dosage forms
“would be gastrically retained in vivo” for several hours. “There is no in vivo data that’s
presented, there is no swelling data that’s presented and to be fair, at the time this was an
emerging art and one of skill would look at these systems rather skeptically and would want
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to see some evidence that these systems are actually gastric retained.” Tr. 1012:6-23;
1024:10 – 1025:4.
Also with respect to motivation, Depomed contends that International Patent
Publication No. WO 01/37812 (“WO ‘812”) teaches away from a matrix dosage form being
retained in the stomach without an attached membrane. The ‘812 application is a
combination system, comprising at least two components, the matrix and a membrane,
affixed or attached thereto. What this patent teaches is that when taken separately, neither
of the matrix nor the membrane would retain in the stomach more than a conventional
dosage form, but when the matrix is combined with the membrane, it achieves gastric
retention. Tr. 653:3-25; 980:18-981:6.
WO ‘812 states:
The basic concept underlying the delivery system of the present invention is
the provision of a combination system, comprising at least two components,
namely the matrix and the membrane affixed or attached thereto. Taken
separately, neither the matrix nor the membrane would retain in the stomach
more than a conventional dosage form.
DTX 229, at Gralise_JDG_00002882.
Defendant argues that WO ‘812 does not “teach away” from a matrix system
because it does not “criticize” swellable gastric-retained dosage forms. However, “[a]
reference may be said to teach away when a person of ordinary skill, upon reading the
reference, would be discouraged from following the path set out in the reference, or would
be led in a direction divergent from the path that was taken by the applicant.” Galderma
Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013). WO ‘812 would tell a
POSA that “a matrix alone may not be sufficient to achieve gastric retention” and would
teach away from the matrix system of the patents. Trial Tr. 979:20 – 981:10; DTX00229.
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(iii) Motivation – WO ‘128
For the asserted ‘332 and ‘992 patent claims, Dr. Flanagan relied on WO ‘128 in
addition to WO ‘107 as the primary reference in rendering his obviousness opinion. Tr.
625:9-14. As Dr. Mayersohn described, WO ‘128 is directed to “a new dosage form for
highly water soluble medicaments, such as the antidiabetic metformin, which provides for
extended release of the drug and prolonged gastric residence which enables efficient
delivery of drugs normally absorbed in the upper gastrointestinal tract, and to a method for
preparing such dosage form.” Tr. 698:8-14; DTX 236 at GRALISE_JDG_00000057. Dr.
Felton notes that “[t]he WO ‘128 application is focused on gastro retentive delivery system
of metformin hydrochloride.” Tr. 975:16-21.
As noted above, a POSA in 2001 would have had a general motivation to develop
and extended release gabapentin dosage form. However, as with the WO ‘107 application,
there are a number of factors that weigh against finding that a POSA would be motivated to
combine gabapentin with the dosage form of WO ‘128, many of them being set forth above.
Further, while focused on metformin hydrochloride, WO ‘128 also contains a
lengthy list of other potential drugs that may be employed in the formulation. Gabapentin
is not among them, despite Neurontin’s status at the time of being a blockbuster drug.
According to Dr. Felton, a POSA reviewing this list would be skeptical that any or all of
those drugs would be suitable in the described dosage form because there is no data for any
drug other than metformin. Tr. 978-979. Furthermore, Dr. Felton points out that among the
drugs listed is insulin, which cannot be absorbed orally. Tr. 979.
As noted earlier, gabapentin and metformin are not interchangeable. Tr. 983:2-8.
Testimony at trial showed that there are significant difference between the two, discussed
75
infra. These differences along with the limited pharmacokinetic data in WO ‘128 are
contrary to the assertion that there is a clear motivation to combine the WO ‘128 reference
with the gabapentin IR reference to produce the inventions of the asserted claims of the
‘332 and ‘992 patents.
d. Reasonable Expectation of Success
(i) Gabapentin Patents-WO ‘107 in view of Rowbotham
Dr. Flanagan testified that one of ordinary skill “would have taken gabapentin and
put it into one or more of Depomed’s WO ‘107 formulations and they would have had a
reasonable expectation that they would have had an efficiently absorbed gastric retained
formulation.” Tr. 577:5-8. Dr. Flanagan noted that while gabapentin is not one of any
number of drugs mentioned in WO ‘107, one of skill in the art would have used that
formulation for gabapentin because the reference is: (1) directed toward soluable drugs and
gabapentin is a soluable drug; and (2) its directed to controlled release by diffusion and for
gastric retention and for a drug that is absorbed high in the intestinal tract, and gabapentin is
such a drug. Tr. at 557:9-25.
Exemplary drugs identified by WO ‘107 are metformin hydrochloride, captopril,
erythromycin lactobionate, ranitidine hydrochloride, sertraline hydrochloride and
ticlopidine hydrochloride. DTX 234 at GRALISE_JDG_0000844. Focusing on metformin
specifically, Dr. Flanagan testified that if a POSA replaced metformin with gabapentin in
WO ‘107, that person could reasonably expect to obtain similar release characteristics and
once-daily dosing. Tr. 565:2-9. He further explained that this is because of the similarities
between the two drugs: “[T]hey're both highly soluble drugs, they both have saturable
transporters and they're both absorbed high in the gastrointestinal tract. So putting them into
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a formulation that would maintain them in the gastric environment would insure that they
don't release drug beyond their window, narrow window of absorption and when the
formulation is releasing those drugs slowly, they -- the saturable transport would not be
saturated and both drugs would be efficiently absorbed.” Tr. 565: 11-19.
Dr. Flanagan further testified that a person of ordinary skill would have expected a
therapeutic effect for the controlled release formulation as compared to the known
immediate release formulation. Tr. 577:19-578:1. Effective daily doses (e.g., 300 mg to
4,800 mg) of gabapentin to treat epilepsy or neuropathic pain with an immediate release
formulation were well known to those of skill in the art in October 2001. DTX 267 at
GRALISE_JDG_ 00000126-28; DTX 313 at GRALISE_JDG_00000451,
GRALISE_JDG_00000453-56. According to Dr. Flanagan, both 300 mg and 600 mg oncedaily dose strengths would have been a natural starting points for one skilled in the art for
creating a once-a-day formulation. Tr. 619:21- 620:1, 622:1-14.
However, substantial evidence was presented at trial that counters a finding of a
reasonable expectation of success. For example, there are the studies conducted by Dr.
Gidal and others that indicated that there was significant variability in gabapentin
absorption between persons. The results of one study were published in 2000 in Inter- and
Intra-subject variability in gabapentin absorption and absolute bioavailability, Gidal et al.,
Epilepsy Research 40 (2000) PTX 275 at 123-127. This states:
The results of the present studies do highlight the point that the use of
‘average’ population kinetic data may be misleading in situations where
substantial variability exists. In other words, although the average variability
of a 600 mg oral dose of gabapentin was 49%, individual subjects may vary
greatly (5-74%). The clinical implication is that ‘typical’ or ‘usual’ doses are
likely to result in quite different plasma concentration in individual patients.
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Indeed, similar observations were noted by Beydoun et al. in an efficacy trial
of gabapentin monotherapy.
PTX 275 at DEPOACT0970237.
Actavis’s expert Dr. Mayersohn acknowledged the inter-person variability noting
that the variability was three fold even after excluding “outliers.” Tr. 735:1-5; 735:21 –
736:6. Dr. Gidal noted that there were several individuals who showed less bioavailability
of gabapentin than that suggested by the product information, indicating that the intersubject variability in gabapentin absorption is significant. Tr. 825:25 – 826:13. Actavis
suggests that variability in gabapentin absorption would be clinically significant and points
to the successful immediate release formulation of gabapentin, Neurontin. While variable
absorption has not prevented the success of Neurontin, Defendant’s expert Dr. Sinatra,
explained that Neurontin is, in fact, ineffective in some patient, Tr. 898:22 – 899:10, which
suggests that inter-person variability in gabapentin absorption does have therapeutic
consequences.
Echoing many of its arguments regarding motivation, Depomed argued that a POSA
would not have had a reasonable expectation of success for the following reasons:
First, gabapentin and metformin are not interchangeable;
Second, “[g]abapentin is known to be sensitive to acidic environment of the
stomach and so one would not want to put a drug that degrades in acid in the stomach
where it’s going to reside for a number of hours;”
Third, gabapentin may not be made available in its narrow window of absorption.
There is no in vivo data in the WO ‘107 reference showing that a dosage form would be in
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fact gastrically retained or that a gabapentin containing dosage form would be gastrically
retained;
Fourth, gabapentin’s release rate may not avoid saturation of absorption
transporters;
Fifth, food affects gabapentin absorption;
Finally, there was a lack of known correlation between gabapentin plasma
concentration and therapeutic effect. Tr. 989:7 – 990:19; 990:25 – 992:24.
Further, it also appears that successfully putting gabapentin into the WO ‘107
dosage form would require more than routine experimentation. Dr. Felton testified as to the
differences between gabapentin and metformin that would impact the ability to substitute
gabapentin for metformin in the WO ‘107 dosage form: (i) “Metformin is a cation, so it’s
positively charged, not only in the body at physiological pH, but also in the low pH of the
stomach. Gabapentin is a zwitterion, it has a positive charge and a negative charge.” Tr.
982:23 – 983:8; 983:21 – 984:4; (ii) as mentioned earlier, gabapentin degrades into lactam;
metformin does not; (iii) metformin is more than twice as soluable as gabapentin. 730:5-14;
953:8-10. These differences would impact the swelling, retention and release rates per Dr.
Felton’s testimony: “[T]he gastric retention mechanism, the swelling, is also related to the
drug release and so adjusting the formulation to slow or increase the rate of the release
could actually affect and probably would actually affect the swelling and, therefore, the
gastric retention properties. ... If you change the formulation to change the release rate,
because the formulation swells and that’s how it achieves gastric retention, by changing the
composition of the tablet, the swelling behavior could change.” Tr. 984:14 – 985:9; 986:311.
79
Dr. Hopfenberg explained that metformin and gabapentin would be released
differently from a dosage form. Two factors drive diffusion: (a) solubility of the drug in the
swollen matrix; (b) “diffusion coefficients” or diffusivity that provides how fast the drug
can move through the dosage form. As noted, gabapentin has a solubility more than twofold less than that of metformin (135 mg/ml versus > 300 mg/ml). As Dr. Hopfenberg
testified, diffusivity is related to the bulkiness of the molecule. Metformin is linear and
rather small and would be more mobile than gabapentin which is a more bulky molecule
with a ring structure that gives additional steric hindrance. Thus, metformin would release
at a much higher rate than gabapentin. Tr. 951:21 – 952: 19.
As such, as Depomed contends, contrary to Defendant’s assertions, it would not be
simply a matter of routine optimization to fine-tune gabapentin in the dosage form as
compared to metformin. “[T]here would be a need to adjust the formulation so that the
release of the gabapentin would be at some different rate and that release could affect the
swelling, and therefore, the gastric retention.” 985:10-19, 986:3-11.
There is also evidence that the pharmacokinetic parameters for metformin and
gabapentin would be different. Tr. 1047:6-9. Dr. Derendorf testified that gabapentin and
metformin differ from each other with respect to each of the pharmacokinetic properties:
absorption, distribution and elimination, such that the exposure that would result from these
two products would be quite different. Tr. 1039:13-22.
With respect to absorption of the drug, as of 2001, it was known that gabapentin is
taken up by transporters. However, the mechanism of absorption of metformin was unclear.
Tr. 1041:8 – 1042:9; PTX 556 at 1018. Dr. Derendorf testified that if metformin and
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gabapentin exhibit different absorption mechanisms, then he would not expect them to have
similar pharmacokinetic behavior. Tr. 1042:10-15.
Dr. Derendorf testified that, while the precise absorption window of either drug is
unknown, the absorption window of gabapentin is likely not identical to that of metformin.
Tr. 1042:22 – 1043:11. Even if the absorption window were the same, Dr. Derendorf
would expect there to be differences in absorption because the transporters would be
different; they would have different affinity and therefore different efficiency in absorbing
the drugs. Tr. 1043:12:23. Dr. Derendorf explained that one would obtain different types of
absorption profiles depending on the transporter in use. The profile would depend on the
affinity of the transporter for the drug and the capacity of the transporter for the drug—how
much drug the transport can move into the blood stream. Tr. 1044:6-20. In 2001, the
affinity and capacity of L-type amino acid transporter for gabapentin was unknown and the
metformin transport mechanism was unclear. Tr. 1044:21 – 1045:2.
Looking at the pharmacokinetic property distribution, there is evidence that
distribution of gabapentin and metformin is different. Metformin has a 10-fold larger
volume of distribution in tissues resulting in low plasma concentration, unlike gabapentin.
Tr. 1045:3-15.
Dr. Derendorf explained that difference in distribution changes the
pharmacokinetic profile obtained. For example, the Cmax value depends on the volume of
distribution and the higher the volume of distribution, the lower the Cmax for the same
amount of drug that enters the system. Tr. 1046:16-25.
With respect to the third pharmacokinetic property, elimination, Dr. Derendorf
testified that although both metformin and gabapentin are eliminated by the kidneys, the
mechanism of elimination is different. Whereas gabapentin is mainly eliminated by
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glomerular filtration, which does not involve transporters, metformin is eliminated by
tuberous secretion, which involves transporters. Metformin is therefore eliminated at a
much higher rate than gabapentin. Dr. Derendorf opined that one of skill cannot expect two
drugs with different eliminations to have similar pharmacokinetics. Tr. 1046:1-16. Such
pharmacokinetics are contrary to a clear reasonable expectation of success on combining
WO ‘107 with gabapentin immediate release references.
(ii) ‘332 and 992 patents--WO ‘128 in view of Rowbotham.
The WO ‘128 does not provide pharmacokinetic information for gabapentin,
however Dr. Mayersohn testified that a person of ordinary skill in the art would have a
reasonable expectation of achieving a similar effect on the pharmacokinetics of gabapentin
by putting gabapentin into the WO ‘128 dosage form – i.e., reduced Cmax, longer Tmax and
similar AUCinfinity compared to the immediate-release product. Tr. 705:19-706:1, 715:21717:18, 718:16-21; 717:22-718:11. Dr. Mayersohn based his opinion with respect to this
expectation of success upon the properties that both gabapentin and metformin were known
to have in common, Tr. at 718:3, -- high water solubility, saturable absorption, and a limited
window of absorption high in the gastrointestinal tract. Tr. 563:19-24; 5/15/2014 Tr.
698:17-20. Dr. Mayersohn opined, based on these properties, that one of ordinary skill in
the art would have reasonably expected that the behavior of metformin and gabapentin
would be the same when put into the WO ‘128 dosage form. Tr. 715:21-717:18; see also
Tr. 626:4-628:18, 628:20-22.
However, as discussed above, a deeper look into the evidence reveals significant
differences between metformin and gabapentin that undercut Dr. Mayersohn’s opinion here.
The evidence discussed in the prior section shows that metformin and gabapentin exhibit
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substantial differences that would affect swelling, retention and release rates. Tr. 984-989.
There also exists differences in solubility, pharmacokinetic properties, and they exhibit
different absorption mechanism. As such, the Court cannot conclude that Actavis has met
its burden to establish that there would exist a reasonable expectation of success.
e. Secondary Considerations
(i) Unmet Need
The parties have stipulated that Gralise embodies the asserted claims of the ‘927,
‘989, ‘756, ‘332 and ‘992 Patents. Gralise was approved in 2011 and was the first
sustained release gastric retained oral dosage form for gabapentin. Tr. 679:8-11.
Experts on pain management testified for each side. Depomed’s expert, Dr.
Michelle Brown, who was accepted as an expert in treating neuropathic pain, testified that a
long-felt need existed for a controlled release formulation of gabapentin to address the
issues of compliance and minimizing side effects. Tr. 866-886. Gralise met that need. Tr.
870:1-7. Among other things, Dr. Brown also relied on her clinical experience, which
includes her continuous treatment of neuropathic pain for twenty-two years, during which
time she has prescribed numerous drugs, among them both immediate release and
controlled release formulations of gabapentin. Tr. 867:18–868:19.
Actavis’s Dr. Sinatra, while not expressly offering a contrary opinion regarding
long-felt unmet need, testified that in his medical experience there are no compliance
problems with taking immediate release gabapentin because, unlike medications used for
treating undetectable symptoms such as high blood pressure, a patient being treated for pain
would not forget to take their pain medication. Tr. 903:17-904:9. The Court overall,
however, accords Dr. Sinatra’s opinions less weight in light of the fact that he simply has
83
no experience prescribing Gralise. He testimony, based on his personal prescribing habits,
is that his first choice medication for treating postherpetic neuralgia is gabapentin
immediate release. Tr. 896:22-25. When asked why, he states that “it has stood the test of
time”, dosing is well understood, and its “a very safe drug.” Tr. 897:1-10. However, he
admits that Gralise is not available on the formulary at the medical centers where he
practices and, therefore, he has never prescribed extended-release gabapentin. It is not
unreasonable to conclude that where a physician is, for all practical purposes, unable to
prescribe a certain drug, it would influence somewhat that his opinions with respect to the
alternative drugs.
Thus, on balance, the weight of the evidence favors a finding of the existence of a
long-felt, unmet need.
(ii) Failure of Others
Dr. Bockbrader testified that Warner-Lambert was unable to develop a controlled
release dosage form of gabapentin and was skeptical of developing a controlled-release
dosage form. Tr. 748:14-19. This attempt by Warner-Lambert to make a controlled release
formulation of gabapentin, however, occurred at a time before it was known that gabapentin
was absorbed high in the gastrointestinal tract and/or that gabapentin was absorbed through
saturable transporters. Tr. 768:7-21, 770:15-771:4, 768:22-770:3.
Dr. Felton reviewed lab notebooks and related documents produced by Andrx,
which tried but failed to develop an extended release form of gabapentin from 1999 to
2001. Tr. 1001:14-25, 1002:22-1005:10. Andrx’s formulations, however, were not
designed to be gastric retained. 1017:23-1018:10, 1019:12-1020:6. As the same
formulations were also used to test delivery of Andrx’s proprietary gabapentanoid prodrug
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(which has a different absorption profile than gabapentin not limited to the upper
gastrointestinal tract), Tr. 1019:12-1020:6, Defendant suggests that Andrx was merely
using the gabapentin formulations as a baseline to compare with their proprietary
gabapentanoid prodrug.
While there is some evidence that there has been failures by others to create a
controlled release gabapentin formulation, the Court finds, given the findings above, this
factor to be relatively neutral in the obviousness analysis.
(iii) Skepticism
Dr. Bockbrader and Dr. Gidal testified that a POSA there was skepticism as of
October 2001 about the feasibility of an effective extended release gabapentin formulation.
As noted above, Dr. Bockbrader testified regarding the skepticism and failure at Warner
Lambert. Tr. 748:14-19 Dr. Gidal testified that, based on the unpredictable
pharmacokinetics, variability in absorption, etc., discussed earlier, he was skeptical that one
could craft a controlled release formulation of gabapentin that would be therapeutically
effective. Tr. 816:24-817:5.
Dr. Gidal similarly also suggested XenoPort, a small biopharmaceutics firm, was
skeptical of a controlled release gabapentin formulation when they decided to develop a
prodrug of gabapentin, gabapentin enacarbil, that bypasses the gabapentin transporters and
uses a different transporter to achieve linear, non-saturable absorption. Tr. 849:3-7, 853:1216; PTX 269 at DEPOACT0958153; PTX 277 at DEPOACT0970277. Dr. Gidal testified,
however, that he was never asked to help develop a controlled release form of gabapentin
for XenoPort and that they only approached him to develop a prodrug. Tr. 860:6-15,
861:14-16.
85
Overall, the Court concludes that there is evidence of some skepticism in the
industry, but the evidence on this factor is not especially compelling.
(iv) Commercial Success
Gralise was launched in October 2011. Since that time, Plaintiff’s economics
expert, Dr. Nicholson, explained that that there has been in increase in monthly
prescriptions from about 3,000 in December 2011 to 23,000 in December 2013. Tr.
1069:5-16. Similarly, wholesale sales and net sales have seen corresponding increases over
that time as well. Tr. 1069:20 - 1070:25.
Gralise competes in the marketplace with Neurontin, generic gabapentin, Lyrica,
Horizant, Lidoderm, Cymbalta, Savella and Qutenza, which are drugs approved for PHN
and related indications. PTX00703 at slide 3; Tr. 1067:2-17. The market is mature and
competitive. Tr. 1068:2-14. Defendant’s expert Dr. Sullivan calculated that Gralise has a
very small market share of 0.24% in July 2013. Tr. 1198:19-1199:2. Market share has
increase slightly year to year since 2011 (0.16% in 2012 to 0.24% in 2013), but Dr. Sullivan
testified that the change was not “meaningful” and was effectively rounding error. 1198:16
- 1199:2.
Dr. Nicholson also testified about his net present value analysis, which consists of
deriving the revenues and the costs and the profits through each year of a product's life. Tr.
1071-72. According to Dr. Nicholson, companies use net present value to evaluate whether
to develop or invest in products. Tr. 1071. Dr. Nicholson’s analysis shows that Gralise’s
net present value will turn positive in its 10th year on the market, which means that at that
point Gralise will have recouped its R&D costs and it will have exceeded investors’
required rate of return on pharmaceutical investments, and it will continue to generate
86
f. Conclusion as to Whether the Gabapentin Patents Would Have Been Obvious
Defendant contends that the asserted claims of the Gabapentin Patents would have
been obvious to one of ordinary skill over the WO ‘107 in view of an article by Michael
Rowbotham along with the knowledge of a person of ordinary skill in the art. Actavis also
contends that the asserted claims of the ‘332 and ‘992 Patents would have been obvious to
one of ordinary skill over WO ‘128 and the Rowbotham article along with the knowledge
of a person of ordinary skill in the art.
Approaching the question of obviousness from the perspective of a POSA as of
October 2001 seeking to develop a controlled-release formulation of gabapentin, the Court
finds that Actavis has failed to carry its burden of clearly demonstrating the obviousness of
the Gabapentin Patents.
As an initial matter, particularly to the extent that Defendant relies on WO ‘107, the
Court agrees with Plaintiff that Defendant’s case suffers from impermissible hindsight bias.
Importantly, an “invention must be viewed not with the blueprint drawn by the inventor,
but in the state of the art that existed at the time. The invention must be evaluated not
through the eyes of the inventor, who may have been of exceptional skill, but as by one of
‘ordinary skill.’” Interconnect Planning Corp. v. Feil, 774 F.2d 1132, 1138 (Fed. Cir.
1985). The prior art shows that although gastro-retentive drug delivery systems were an
emerging art and not well developed, there were many possible approaches to a gastroretentive drug delivery system. See generally Hwang reference, DTX 222. Defendant
failed to establish by comparison the suitability of the WO ‘107 dosage form over other
potential approaches. Dr. Flanagan admitted that although the Hwang reference taught
88
multiple approaches to gastric retention, he did not address any of those approaches. Tr.
661:2-7.
Additionally, the Court finds there exists evidence, detailed above, that would cast
doubt on the motivation of a POSA to put gabapentin in the dosage forms of the prior art,
for example food effect and degradation of gabapentin in lactam. Similarly, while there
may have existed a general motivation to create a once-daily gabapentin formulation to
improve compliance and possibly reduce side effects, certain unique characteristics of
gabapentin, detailed above, may have dissuaded a POSA from attempting to develop an
effective extended release gabapentin formulation and weigh against a finding of
reasonable expectation of success.
In sum, based upon the findings set forth above, the Court finds that Defendants
have not met their burden to show that the Gabapentin Patents are invalid for obviousness.
5. The ‘962 Patent
The ‘962 Patent addresses the problem of developing tablet shapes to enhance the
gastric retention of swellable controlled-release oral dosage forms. Tr. 933:19 – 934:2;
505:9-12. The specification explains that, although dosage forms that swell to sizes that
will prolong the residence time in the stomach, the tablet could still be expelled from the
stomach depending on the tablet’s orientation in the stomach. JTX 1 at col. 2. l. 52 - col. 3,
l. 5. More specifically, the specification of the ‘962 Patent states:
Even with swelling, a certain proportion of particles can pass through the
pylorus regardless of whether the subject is in the fed mode or the fasting
mode, if the particles become oriented when in the vicinity of the pylorus
such that their longest dimension is in alignment with the pyloric axis. This
is particularly true of tablets or caplets (cylindrical tablets with rounded
ends) that are elongated in shape to facilitate swallowing. When dosage
forms such as these swell due to imbibition of water, one dimension may
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achieve a length great enough to exceed the pyloric opening while the others
may be significantly smaller. The dosage form will thus be retained in the
stomach only if the form is oriented with the long dimension transverse to
the pyloric opening. Accordingly, for a certain percentage of the
administered units of these swellable forms, prolonged retention in the
stomach is not achieved and the beneficial effect of the swelling is lost.
There is thus only a limited assurance that the swelling will result in gastric
retention of the dosage form.
Id. at col. 3, ll.1-19.
The specification explains that “by using a solid water-swellable dosage form of a
particular shape, the proportion of these dosage forms that escapes through the pylorus due
to a fortuitous orientation at the pylorus can be reduced or eliminated entirely while still
having a dosage form that is easily swallowed.” Id. at col. 3, ll. 23-27. The specification
goes on to state in the summary of the invention that “[t]he shape that achieves this result is
a non-circular and non-spherical shape which, when projected onto a planar surface, has
two orthogonal axes of different lengths . . . .” Id. at col. 3, ll. 27-30. The patent claims two
specific dosage form shapes as defined by the planar projection of the solid monolithic
matrix: “. . . and wherein said matrix has a shape which when projected onto a plane, is
either an oval or a parallelogram.” JTX001,‘962 Patent, col. 11, ll. 24-26 .
There appears to be no dispute that the priority date of the asserted claims of the
‘962 Patent is June 20, 2000. Def. Proposed Findings ¶ 20; Pl. Proposed Findings ¶ 1012.
a. Prior Art
The WO ‘107 application and Hwang references are discussed above.
International Publication No. WO 98/56360 (“WO ‘360”), referred to by Dr.
Flanagan in his testimony, describes film-coated oral dosage forms for the transit of drugs,
known to irritate the esophagus, to the stomach where they dissolve to release the drug.
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Trial Tr. 681:18 – 682:3; Tr. 943:14-21. The dosage form of the WO ‘360 is designed to
dissolve upon reaching the stomach to prevent direct contact of the tissues of the mouth,
pharynx and esophagus with the active ingredient and to allow proper absorption of the
active ingredient at the appropriate site. As relevant here, WO ‘360 discloses a
“pharmaceutical formulation in a generally oval shape including, but not limited to, oval,
modified oval and caplet-shaped form.”
b. Whether the ‘962 Patent is Would Have Been Obvious
The ‘962 Patent contains 27 claims, four of which are asserted in this action against
the 600 mg ANDA product. Claim 1 is the only independent claim, and recites a controlledrelease dosage form for releasing a drug into at least a portion of a region defined by the
stomach and upper gastrointestinal tract. The controlled-release oral dosage form recited
by claim 1 consists essentially of a (1) solid monolithic matrix with drug contained therein,
(2) that is non-circular in shape and has two orthogonal axes of unequal length, (3) where
the matrix swells in an unrestricted manner along both axes upon imbibition of water, (4)
the longer axis of the unswollen matrix does not exceed 3.0 centimeters, (5) the shorter axis
of the matrix achieves a minimum length of 1.2 centimeters within one hour of immersion
in water, and (6) the matrix projects the shape of an oval or parallelogram onto a plane.
JTX 1 11:14-25; Tr. 934:23 – 935:20.
The remaining claims, 2-27, cover variants of the invention recited in Claim 1.
JTX001 at 11:13 – 12:64. Claims 5, 8, and 10 depend upon Claim 1, while Claim 13 also
depends upon Claim 10. The ‘962 Patent claims two specific dosage form shapes as defined
by the planar projection of the solid monolithic matrix: “. . . and wherein said matrix has a
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shape which when projected onto a plane, is either an oval or a parallelogram.” JTX 1 col.
11 ll. 24-26.
Actavis argues that the asserted claims 5, 8, 10 and 13 would have been obvious to
one of ordinary skill over the WO ‘107 application along with the knowledge of a person of
ordinary skill in the art. As noted, all of the asserted claims depend from claim 1.
Defendant’s expert, Dr. Flanagan, opined that each limitation of claim 1 of the ‘962 patent
is disclosed or suggested by WO ‘107. In contrast, Dr. Hopfenberg testified that WO ‘107
fails to teach or suggest at least two elements of Claim 1 of the ‘962 Patent to one of
ordinary skill in the art. Tr. 944:18-22. Those two elements are (i) “wherein said matrix
has a shape which when projected onto a plane, is either an oval or a parallelogram”; and
(ii) “the shorter such axis achieving a minimum length of 1.2 cm within one hour of
immersion of said dosage form in water.” Tr. 944:18 – 945:2; JTX001 at 11:22-25.
As to the first element, it is undisputed that WO ‘107 does not disclose an ovalshaped or parallelogram-shaped dosage form. Tr. 633:8-15. Prior art WO ‘360, on the
other hand, discloses an oval dosage form. DTX 235. However, WO ‘360 is a dosage form
designed disintegrate, and does not swell, in the stomach. Tr. 942:24-25; 681:18-21. As
such, the Court agrees with Plaintiff that WO ‘360 is of no consequence.
As to the first second, the Court again agrees with Depomed that it is not enough to
say, as Dr. Flanagan testified (see Tr. 631:7-18) that WO ‘107 suggests the 1.2 centimeter
limitation to one of skill in the art because of the disclosure that the WO ‘107 dosage forms
swell to “at least twice their unswelled volume” as a means of “promot[ing] gastric
retention in the fed mode.” Tr. 937:16 – 938:19. Dr. Flanagan’s opinion does not address
the time limitation coupled to the 1.2 centimeter element of the ‘962 Patent inventions, i.e.,
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“the shorter [] axis achieving a minimum length of 1.2 cm within one hour of immersion of
said dosage form in water.” Tr. 938:2-8.
Further, Dr. Flanagan does not point to an initial dimension of the short axis of the
WO ‘107 dosage forms, nor to those dosage forms’ rate of swelling. Tr. 630:12 – 633:7.
Nor does he explain how one of skill would link (i) the disclosure that the WO ‘107 dosage
forms swell to “at least twice” their volume, to (ii) an increase in the length of those dosage
forms’ shortest dimension. Tr. 630:12 – 633:7. According to Dr. Hopfenberg, a doubling
of the volume of the WO ‘107 dosage form can only result in a doubling of its shortest
linear dimension where all other orthogonal dimensions remain constant. Tr. 938:9-19.
Such a circumstance would not be consistent with the unrestricted swelling required by
Claim 1 of the ‘962 Patent. Tr. 938:15-19.
The matrices of the claimed ‘962 Patent dosage forms not swell in an unrestricted
manner, they further swell to a specific dimension after a specific period of time. Tr. 937:16
– 938:8. The latter, additional requirement on the rate and extent of unrestricted swelling is
not disclosed by WO ‘107. Tr. 631:9-12; 937:16 – 938:8. WO ‘107 does not say, for
example, that its swollen dosage form achieves a minimum dimension of 1.2 centimeters
after one hour of immersion as recited by Claim 1 of the ‘962 Patent. 631:9-12; Tr. 937:16
– 939:4.
Notably, Dr. Flanagan’s opinion rests on his view that the ‘962 Patent inventions
require administration to a fed stomach. Tr. 631:15- 21. The ‘962 Patent, however, does
not a recite a claim element directed to gastric retention in the fed mode. Tr. 936:24-937:5.
Rather, the ‘962 Patent specification states that “the dosage forms of the present invention
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find utility when administered to subjects who are either in the fed mode or the fasting
mode.” JTX 1, col 7, ll. 9-11.
Contrary to Dr. Flanagan’s testimony, the Court finds, based upon the testimony of
Drs. Hopfenberg and Derendorf, that a POSA could not arrive at the invention of the ‘962
patent by routine optimization of the dosage forms disclosed in WO ‘107. As Dr.
Hopfenberg points out, all of the elements of claim 1 not disclosed. Tr. 938:20 – 939:4 .
Further, as Dr. Derendorf explained, WO ‘107 contains no in vivo or pharmacokinetic data
demonstrating the extent to which the dosage forms are gastric retained.
Thus, for the reasons above, the Court finds that Actavis has failed to carry its
burden of establishing by clear and convincing evidence that the ‘962 patent is invalid
based upon obviousness.
G. INDEFINITENESS
Defendant argues that the asserted claims of the ‘280 patent are invalid because they
are indefinite. Specifically, Defendant points to that part of Claim 1 which recites that the
claimed dosage form must swell to a “size exceeding the pyloric diameter in the fed mode.”
JTX 2; Stip. Facts¶ 53. All of the other asserted claims of the ‘280 Patent depend from
claim 1 and, therefore, are also include this limitation.
Plaintiff argues that Defendant’s indefiniteness claim is not properly before the
Court. Shortly before trial, Actavis filed a motion seeking to amend their invalidity
contentions to add a contention that the ‘280 patent is invalid because it is indefinite. The
Court denied that motion, finding that Actavis unreasonably delayed in bringing it and that
no good cause existed to permit the amendment. As such, the Court need not reach the
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issue and denies relief to Actavis to the extent it seeks a finding of invalidity of the ‘280
patent based on indefiniteness.
Nevertheless, had the Court been required to address the question, for the reasons
below, the Court would have found that Defendant would not have met its burden to show
that the ‘280 patent was invalid as indefinite.
1. Legal Standard
To be sufficiently definite, a patent specification must “conclude with one or more
claims particularly pointing out and distinctly claiming the subject matter which the
applicant regards as his invention.” 35 U.S.C. § 112, ¶ 2. The boundaries of the claim must
be discernible to one skilled in the art based on the language of the claim, the specification,
and the prosecution history, as well as that person's knowledge of the relevant field of art.
See Halliburton Energy Servs., Inc. v. M–ILLC, 514 F.3d 1244, 1249–51 (Fed. Cir. 2008).
The Supreme Court recently articulated a new standard for indefiniteness, holding that “a
patent is invalid for indefiniteness if its claims, read in light of the specification delineating
the patent, and the prosecution history, fail to inform, with reasonable certainty, those
skilled in the art about the scope of the invention.” Nautilus, Inc. v. Biosig Instruments, Inc.,
134 S.Ct. 2120, 2124 (2014). The Federal Circuit has noted that “because claim
construction frequently poses difficult questions over which reasonable minds may
disagree, proof of indefiniteness must meet an exacting standard.” Haemonetics Corp. v.
Baxter Healthcare Corp., 607 F.3d 776, 783 (Fed. Cir. 2010) (quotations omitted).
However, “[i]f the meaning of the claim is discernible, even though the task may be
formidable and the conclusion may be one over which reasonable persons will disagree, we
have held the claim sufficiently clear to avoid invalidity on indefiniteness grounds.” Exxon,
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265 F.3d at 1375. Because a patent is presumed to be valid, the evidentiary burden to show
facts supporting a conclusion of invalidity for indefiniteness is one of clear and convincing
evidence. See Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1348 (Fed. Cir.
2005).
2. Analysis
As noted earlier, the pylorus is the structure in the stomach that regulates materials
leaving the stomach into the intestine. Tr. 152:16-153:1. When food is in the stomach, the
pylorus generally stays to prevent food from moving into the intestine before the
destructive forces of the stomach have a chance to break the food down into smaller
particles. Tr. 152:19-23. The pylorus will periodically open to allow some of the stomach
contents to pass into the intestine, typically the smaller, broken-down particles. Tr. 235:919. While the reference to “pyloric diameter in the fed mode” in the ‘280 Patent claims
does not explicitly state whether it refers to the pyloric diameter when the pylorus open or
closed, in context it is clear that it is referring to the diameter when the pylorus is in an
open, relaxed state.
With regard to indefiniteness, the Court first notes that 3 different courts, including
this one in this case, have construed the claim language that Actavis alleges make the patent
indefinite. Judge Hamilton construed it in Depomed, Inc. v. Lupin Pharm., Inc. et al., No.
C-09-05587 PJH (N.D. Cal. 2011) and Judge Breyer construed it in Depomed, Inc. v. Ivax
Corp., No. C-06-00100 CRB (N.D. Cal. 2006). This would indicate that the patent does not
fail to inform, with reasonable certainty, those skilled in the art about the scope of the
invention.
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Furthermore, guidance can be found in the specification. One of skill in the art reads
the following passage from the ‘280 Patent specification for guidance as to the particle size
that promotes retention in the fed stomach: “Indigestible particles greater than the size of
the pylorus are retropelled and retained in the stomach. Particles exceeding about 1 cm in
size are thus retained in the stomach for approximately 4 to 6 hours. The dosage form of the
present invention is designed to achieve the minimal size through swelling following
ingestion during the fed mode.” ‘280 Patent, JTX002, col. 11, l. 66 to col. 12, l. 5. Thus,
this statement indicates that (i) indigestible particles “greater than the size of the pylorus”
that “exceed[] about 1 cm in size” are retained in the stomach, and by extension (ii) the
swellable dosage forms claimed in the ‘280 Patent are intended to obtain this “minimal size
. . . following ingestion during the fed mode.”
Extrinsic evidence provides guidance as well. According to Dr. Annunziata, the
overall diameter of the human pylorus during the fed state for the brief time periods it is
open is approximately one centimeter. Tr. 245:25 – 246:16. Also, one study, taking into
account the broader variability between individuals, reported the average diameter of the
resting human pylorus as 12.8 ± 0.7 millimeters. Tr. 244:16-19, 259:15-25; PTX000245 at
DEPOACT0114761.
Consequently, based on the above, the Court does not find the ‘280 patent to be
invalid as it does not “fail to inform, with reasonable certainty, those skilled in the art about
the scope of the invention.” Nautilus, 134 S.Ct. at 2120.
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H. CONCLUSION
For the reasons above, the Court finds in favor of Plaintiff on all claims in this case.
An appropriate judgment accompanies this Opinion.
/s/ JOEL A. PISANO
United States District Judge
Dated: August 18, 2014
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