United States District Court, D. New Jersey
CLAIRE C. CECCHI UNITED STATES DISTRICT JUDGE.
a consolidated Hatch-Waxman patent infringement action
brought by Plaintiff Sebela International Limited
("Sebela"). The Defendants in the consolidated
action are Actavis Laboratories FL, Inc., Actavis Pharma,
Inc., Andrx Corp., and Actavis, Inc. (collectively,
"Actavis"), and Prinston Pharmaceutical Inc., Solco
Healthcare U.S., LLC, and Huahai U.S. Inc. (collectively,
has asserted three patents against Defendants: U.S. Patent
Nos. 7, 598, 271 (the "'271 patent"), 8, 658,
663 (the '"663 patent") and 8, 946, 251 (the
"'251 patent"). A fourth patent, U.S. Patent
No. 5, 874, 447 (the "'447 patent") was also
asserted in this litigation. Sebela agreed to withdraw the
claims related to the '447 patent in exchange for
Defendants' agreement not to launch their ANDA products
until June 10, 2017, the expiration date of the '447
patent. ECF No. 175;SOF¶25.
'271 patent is directed to a composition relating to
Sebela's BRISDELLE® paroxetine mesylate product,
the '663 and '251 patents (the "method of
treatment patents") are directed to methods relating to
the same. Noven Therapeutics, LLC ("Noven"), was
the original holder of New Drug Application ("NDA")
No. 204516 for paroxetine mesylate capsules, which are
marketed and sold under the trademark BRISDELLE. SOF ¶
8. On October 16, 2014, Noven sued Actavis for infringement
of the '447, '271, and '663 patents. SOF ¶
12. On August 14, 2015, Noven filed a second suit against
Actavis for infringement of the '251 patent. SOF ¶
13. On November 26, 2014, Noven sued Prinston for
infringement of the '447, '271, and '663 patents.
SOF ¶ 16. On July 7, 2015, Prinston sued Noven for
declaratory judgment on the '251 patent. SOF ¶ 17.
On July 25, 2016, Sebela purchased all benefits and interests
in the '447, '271, '663, and '251 patents and
NDA No. 204516 from Noven, and on September 20, 2016, Sebela
was substituted as Plaintiff. SOF ¶¶ 21-24; ECF No.
have sought approval from the United States Food and Drug
Administration ("FDA") to market generic versions
of paroxetine mesylate. SOF ¶¶ 71, 77. Plaintiff
alleges that Defendants will infringe the patents in suit by
marketing their generic products. Defendants have stipulated
to infringement of the asserted claims of the '663 and
'251 patents. SOF ¶¶ 49-50, 67-68.
Court conducted a bench trial in this matter from December 8,
2016, to December 14, 2016. The Parties submitted post-trial
briefing and proposed findings of fact and conclusions of
law. Closing arguments were held on February 24, 2017, and
March 13, 2017. This Opinion constitutes the Court's
findings of fact and conclusions of law pursuant to Federal
Rule of Civil Procedure 52(a). The findings of fact are based
on the Court's observations and credibility
determinations of the witnesses who testified and a thorough
review of all the evidence admitted at trial. For the reasons
stated herein, the Court finds as follows:
to the '271 patent Plaintiff has not met its burden
of proving infringement by a preponderance of evidence, so
judgment of non-infringement will be entered
in favor of Defendants on the '271 patent.
to the '663 patent. Defendants have met their burden
of proving by clear and convincing evidence that the '663
patent is invalid, so judgment of invalidity will be entered
in favor of Defendants on the '663 patent.
to the'251 patent. Defendants have met their burden
of proving by clear and convincing evidence that the '251
patent is invalid, so judgment of invalidity will be entered
in favor of Defendants on the '251 patent.
Sebela is a Bermuda company with offices located in Hamilton,
Bermuda. SOF ¶ 1. Sebela is the legal owner of all
rights, title and interests in the '271, '663, and
'251 patents. SOF ¶¶ 31, 40, 54. Sebela Ireland
Ltd., a wholly owned subsidiary of Sebela, holds NDA No.
204516. SOF ¶ 22.
Actavis Laboratories FL, Inc. is a Florida corporation with a
place of business at Morris Corporate Center III, 400
Interpace Parkway, Parsippany, New Jersey 07054. SOF ¶
2. Defendant Actavis Pharma, Inc. is a Delaware corporation
with a place of business at Morris Corporate Center III, 400
Interpace Parkway, Parsippany, New Jersey 07054. SOF ¶
3. Defendant Andrx Corp. is a Delaware corporation with a
place of business at 4955 Orange Drive, Davie, Florida 33314.
SOF ¶ 4. Defendant Actavis submitted Abbreviated New
Drug Application ("AND A") No. 207129 to the FDA,
including a paragraph IV certification as to each of the
patents in suit. SOF ¶ 11.
Prinston Pharmaceutical Inc. is a corporation organized and
existing under the laws of Delaware with a principal place of
business at 2002 Eastpark Boulevard, Cranbury, New Jersey
08512. SOF ¶ 5. Defendant Solco Healthcare U.S., LLC is
a Delaware corporation with a principal place of business at
2002 Eastpark Boulevard, Suite A, Cranbury, New Jersey 08512.
SOF ¶ 6. Defendant Huahai U.S. Inc., is a corporation
organized and existing under the laws of New Jersey, with a
place of business at 2001 Eastpark Boulevard, Cranbury, New
Jersey 08512. SOF ¶ 7. Defendant Prinston filed ANDA No.
207188 with the FDA, identifying the BRISDELLE drug product,
and seeking to market and sell within the United States a
generic 7.5 mg paroxetine mesylate capsule product. SOF
¶ 14. ANDA No. 207188 contains a paragraph IV
certification as to each of the patents in suit. SOF ¶
Patents in Suit
The '271 Patent
'271 Patent, titled "Crystalline Paroxetine Methane
Sulfonate, " issued on October 6, 2009 (with
certificates of correction issued on May 17, 2011, and
December 22, 2015), from U.S. Application Serial No. 09/200,
743 (the "'743 application"), which was filed
on November 30, 1998. SOF ¶ 27. The '743 application
was filed as a divisional of U.S. Application Serial No.
08/872, 023 (the "'023 application"), which was
filed on June 10, 1997, and issued as the '447 patent.
SOF ¶ 27. The '743 application included a priority
claim to the '023 application. SOF ¶ 27. The
'271 patent relates generally to a crystalline form of
paroxetine mesylate. SOF ¶ 35; JTX-2. The inventors
listed on the '271 patent are Franciscus Bemardus Gemma
Benneker, Frans Van Dalen, Jacobus Maria Lemmens, Theodorus
Hendricus Antonium Peters, and Frantisek Picha. SOF ¶
January 31, 2001, Synthon, which was the holder of the
'743 application, filed a request for an interference
between the '743 application and U.S. patent No. 6, 063,
927 (the "'927 patent"), which was owned by
SmithKline Beecham and claimed a crystalline form of
paroxetine mesylate described by reference to 8 infrared
("IR") peaks. PFOF ¶¶ 55, 62;
¶ 102. The patent examiner suspended prosecution of the
'743 application on February 21, 2001, PFOF ¶ 64,
and the Board of Patent Appeals and Interferences (the
"BPAI") instituted an interference proceeding (the
"Interference Proceeding") on October 1, 2002, PFOF
¶ 67. Despite the different peak listings, applying the
broadest reasonable interpretation standard, the BPAI
ultimately decided the interference in Synthon's favor.
See PFOF ¶ 77.
The Method of Treatment Patents
'663 patent, titled "Method of Treating
Thermoregulatory Dysfunction with Paroxetine, " issued
on February 25, 2014 (with a certificate of correction issued
on October 7, 2014), from U.S Application Serial No. 12/292,
960 (the "'960 application"). The '960
application was filed on December 1, 2008, as a continuation
of the now abandoned U.S. Application Serial No. 11/499, 586
(the "'586 application"), which was filed on
August 4, 2006. SOF ¶ 36; JTX-3. The '633 patent
relates generally to methods of using paroxetine to treat
thermoregulatory dysfunction. See SOF ¶¶
46-48; JTX-3. The sole inventor listed on the '663 patent
is Patricia Allison Tewes Richards. SOF ¶ 39; JTX-3.
'251 patent, also titled "Methods of Treating
Thermoregulatory Dysfunction with Paroxetine, " issued
on February 3, 2015, from U.S. Application Serial No. 14/157,
992 (the "'992 application"), which was filed
on January 17, 2014. SOF ¶ 51. The '992 application
was a continuation of the '960 application. SOF ¶
51; JTX-4. The '251 patent relates generally to methods
of using paroxetine to treat thermoregulatory dysfunction.
See SOF ¶¶ 62-66; JTX-4. The sole inventor
listed on the '251 patent is Patricia Allison Tewes
Richards. SOF ¶ 53; JTX-4.
specifications of the '663 patent and the '251 patent
are substantively identical. PFOF ¶ 207; DFOF ¶ 26.
The specifications disclose that paroxetine can be used to
treat hot flashes at doses of 9.5 mg down to 0.1, mg. 12/12
Tr. a.m. (Locker) 91:5-11. The specifications contain two
prophetic examples. 12/12 Tr. a.m. (Locker) 91:12-92:3.
Example 1 describes administering paroxetine hydrochloride
and paroxetine mesylate at doses of 1.0, 2.0, 3.0, 4.0, 5.0,
6.0, 7.0, 8.0, and 9.5. DFOF ¶ 14; JTX-3 at 4:63-5:23.
Example 2 describes administering paroxetine hydrochloride,
in anhydrous form, hemihydrate form, and monohydrate form, at
doses of 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and
9.5. DFOF ¶ 15; JTX-3 at 5:25-6:23. In each example the
patent concludes that "[a]fter a few days to weeks, the
symptoms ameliorate." DFOF ¶ 15; JTX-3 at 5:23,
following witnesses appeared and provided live testimony
during the bench trial:
Plaintiffs Fact Witness
Court heard testimony from Mr. Scott Briggs, who is Chief
Commercial Officer at Sebela Pharmaceutical, Inc., 12/13 Tr.
(Briggs) 17:12, and who previously served as Vice President
of Marketing and Sales at Noven, 12/13 Tr. (Briggs) 18:12-13.
Mr. Briggs testified on issues related to the marketing and
sales of Brisdelle.
Plaintiffs Expert Witnesses
Court heard expert testimony from Allan Myerson, Ph.D. The
Court accepted Dr. Myerson as an expert in the fields of
crystallization, crystal and solid forms, pharmaceutical
manufacturing, and industrial applications of
crystallization. 12/8 Tr. a.m. (Myerson) 86:23-87:6. Dr.
Myerson opined on the issues of infringement of the '271
patent and validity of the method of treatment patents.
John C. Jarosz
Court heard expert testimony from John C. Jarosz. The Court
accepted Mr. Jarosz as an expert in the fields of
pharmaceutical economics and economic issues regarding
secondary considerations of commercial success. 12/13 Tr.
(Jarosz) 67:18-68:1. Mr. Jarosz opined on the issues related
to the market performance of Brisdelle.
James A. Simon
Court heard expert testimony from James A. Simon, M.D. The
Court accepted Dr. Simon as an expert on the clinical
treatment, clinical research and management of the symptoms
and medical consequences of menopause, including vasomotor
symptoms. 12/13 Tr. (Simon) 117:23-118:7. Dr. Simon opined on
issues related to the validity of the method of treatment
James R. Woodworth
Court heard expert testimony from James R. Woodworth, Ph.D.
The Court accepted Dr. Woodworth as an expert in the field of
pharmacokinetics, pharmacodynamics, and clinical
pharmacology. 12/14 Tr. (Woodworth) 115:6-14. Dr. Woodworth
opined on issues related to the validity of the method of
Defendants' Expert Witnesses
Robin D. Rogers
Court heard expert testimony from Robin D. Rogers, Ph.D. The
Court accepted Dr. Rogers as an expert in the field of
"solid state chemistry, including crystal engineering,
crystallization, crystal characterization, including by IR
spectroscopy, salts and polymorphism, including the isolation
and characterization of organic compounds and their
applications in pharmaceutical products." 12/9 Tr. a.m.
(Rogers) 23:22-24:8. Dr. Rogers opined on the issues of
infringement and invalidity of the '271 patent.
Brian K. Locker
Court heard expert testimony from Brian K. Locker, M.D. The
Court accepted Dr. Locker as an expert in treating women with
thermoregulatory dysfunction associated with hot flashes.
12/12 Tr. a.m. (Locker) 87:5-13. Dr. Locker opined on the
issue of validity of the method of treatment patents.
Ivan T. Hoffman
Court heard expert testimony from Ivan T. Hoffman CPA/CFF,
CLP. The Court accepted Mr. Hoffman as an expert in the field
of pharmaceutical economics. 12/14 Tr. (Hoffman) 167:9-18.
Mr. Hoffman opined on the issues related to the market
performance of Brisdelle.
following witnesses had video recordings of portions of their
depositions played during the bench trial:
Theodorus Hendricus Antonium Peters
Court saw video testimony from Dr. Theodorus Hendricus
Antonium Peters, one of the named inventors of the '271
Patricia Tewes Richards
Court saw video testimony from Dr. Patricia Tewes Richards
the named inventor of the method of treatment patents.
Court saw video testimony from Dr. Joel Lippman, the Chief
Medical Officer of and a 30(b)(6) witness for Noven.
Confidential Prosecution Documents
have sought to introduce documents from the confidential
record of the Interference Proceeding. Specifically, they
seek to introduce expert declarations filed by Drs. Harry G.
Brittain (DTX-14B) ("Brittain Declaration") and
Wayne Genck (DTX-14C) ("Genck Declaration"), and
excerpts from deposition testimony given by Dr. Bennecker in
a proceeding in the United Kingdom (PTX-880) ("Bennecker
Deposition"). ECF No. 249. On the eve of trial, the
Parties informed the Court that Plaintiff objected to
Defendants' use of these documents on a number of
grounds. Among other things, Plaintiff challenged the
authenticity of these documents on the grounds that, although
they were produced by Sebela on behalf of its predecessor
Synthon, see ECF No. 270 at 2, which had maintained them in
its records, they were not official, certified copies. During
the course of me bench trial, the Court allowed these
materials to be presented and discussed by the Parties,
reserving judgment on their admissibility. Prior to closing
arguments, the Parties submitted briefing on the
admissibility of these documents. ECF Nos. 219, 221, 229,
235. At closing arguments, it became clear that none of the
Parties had actually attempted to obtain certified copies of
the documents from the Patent and Trademark Office
("PTO"), so the Court advised the Parties do so. On
May 1, 2017, over a montii after closing arguments,
Defendants produced a copy of the certified interference file
history, containing the disputed documents including the
Brittain Declaration, Genck Declaration, and Bennecker
Deposition. ECF No. 265. In a May 8, 2017 letter Plaintiff
objected to this production as untimely and argued that its
consideration would not be appropriate as the certified
copies of the documents were not in evidence at the time of
trial. ECF No. 270.
interference documents are part of the file history of the
'271 patent. While Plaintiff argued at trial that the
confidential documents at issue are not part of the file
history because "[w]hen you obtain a certified copy it
will not include the confidential [documents], " 3/13
Tr. 183:8-12, this is clearly not the case, as the certified
record produced by Defendants includes the disputed
confidential documents. Given the dilatory conduct giving
rise to this issue,  and the normal amount of time it takes
to obtain a certified file history, the Court will consider
the certified file history. Furthermore, the production of
the certified copies of the disputed documents merely
confirms the authenticity of the copies that were, in fact,
offered at trial. See Fed.R.Evid. 104(a). Accordingly,
Plaintiffs general objections to the consideration of these
documents is overruled. Objections specific to particular
materials are considered below.
patents in suit involve crystal forms of compounds, infrared
spectroscopy, and the treatment of thermoregulatory
disorders. The following is an introduction to some of the
scientific principles at issue in this litigation.
Crystals and Polymorphism
is a compound that has pharmaceutical uses, including as an
antidepressant and, as claimed in the patents in suit, as a
drug for treating thermoregulatory dysfunction. See, e.g.,
JTX-4 1:51-58. Paroxetine can form a variety of salts,
including paroxetine mesylate, also known as paroxetine
methanesulfonate. See, e.g., JTX-1 at 1:27-33.
of the patent claims at issue relate to different chemical
forms of paroxetine and the arrangement of the molecules
therein. When the molecules are arranged in an ordered,
repeating, regular pattern, they are said to be in a
crystalline form. See 12/8 Tr. a.m. (Myerson) 89:8-17; cf.
12/9 Tr. a.m. (Rogers) 25:14-15. In contrast, when the
molecules are not in an ordered array, they are said to be in
an amorphous form. See, e.g., 12/8 Tr. a.m. (Myerson) 90:1-6;
12/9 Tr. a.m. (Rogers) 25:14-15. In general, amorphous forms
of a compound are less chemically stable and less physically
stable than crystalline forms, so crystalline forms are often
preferred for pharmaceutical use. See, e.g., 12/8 Tr. a.m.
molecules have more than one repeating pattern, or
crystalline form, into which they can be arranged. Each of
the crystalline forms is referred to as a polymorph. 12/8 Tr.
a.m. (Myerson) 92:14-18; 12/9 Tr. a.m. (Rogers) 26:10-22.
Although made up of the same constituent molecules,
polymorphs can have different physical and chemical
properties that are pharmaceutically significant, including
physical stability, solubility, and dissolution. 12/8 Tr.
a.m. (Myerson) 92:24-93:3; see also 12/9 Tr. a.m. (Rogers)
26:25-27:9. When a compound has only one crystalline form, it
may be referred to as "monomorphic." 12/9 Tr. p.m.
is unpredictable. 12/8 Tr. a.m. (Myerson) 94:12-95:2; see
also 12/9 Tr. p.m. (Rogers) 56:20-57:1. Although compounds
with molecular weights below a certain threshold can usually
be crystallized with sufficient effort, 12/8 Tr. a.m.
(Myerson) 95:10-20 ("[T]ypically for compounds with
molecular weights below 1500 [Daltons], if you work on them
long enough you can usually get them to
crystallize----"), it is not possible to predict how
many polymorphs may exist for a given compound, 12/8 Tr. a.m.
(Myerson) 95:21-96:1; 12/8 Tr. p.m. (Myerson) 5:23-6:1; see
also 12/9 Tr. p.m. (Rogers) 51:2-12. A new polymorph may take
decades to be discovered. 12/8 Tr. p.m. (Myerson) 7:5-17;
12/9 Tr. p.m. (Rogers) 53:3-10.
forms may be characterized and described using IR
spectroscopy. IR spectroscopy involves shining IR radiation
at a sample of the compound. Certain frequencies of radiation
are absorbed by the sample as they interact with it. 12/9 Tr.
a.m. (Rogers) 32:24-33:9. Which frequencies are absorbed
depends on the properties of the sample, including the
crystalline structure. A spectrum can be generated by
plotting absorption versus IR frequency. Peaks are observed
in the spectrum at those frequencies where the light was
absorbed by, and therefore did not pass through, the sample.
12/8Tr. a.m. (Myerson) 101:24-102:5, 104:10-15. These peaks
can be used to characterize the crystalline form. 12/8 Tr.
a.m. (Myerson) 102:10-13. These peaks may be sharp or weak.
12/8 Tr. p.m. (Myerson) 22:3-8, 22:23-23:7. Typically, IR
spectra are measured in units of reciprocal centimeters, also
called wavenumbers. 12/8 Tr. a.m. (Myerson) 104:10-15. Often
there is a greater number of peaks between 500
cm-1 and 1500 cm-1, and this region on
the spectrum is referred to as the "fingerprint
region." 12/8 Tr. a.m. (Myerson) 104:16-19; 105:8-12.
are several ways in which variation can be introduced into
the measurement of peaks. These include differences in the
instruments used to generate the spectra, 12/8 Tr. a.m.
(Myerson) 105:17-18; 12/9 Tr. p.m. (Rogers) 40:21-22,
calibration of the instrument used, 12/8 Tr. a.m. (Myerson)
105:18-23, and sample preparation (e.g., mixture of the
sample with a salt, size of the grains of the powder,
concentration of the powder on the disk, use of an oil mull),
12/8 Tr. a.m. (Myerson) 105:24-106:14; 12/9 Tr. p.m. (Rogers)
40:24-25. Instrument resolution can also alter the ability to
distinguish peaks and can affect how the peaks look and their
apparent location. 12/8 Tr. a.m. (Myerson) 107:1-13; see also
12/9 Tr. p.m. (Rogers) 41:7-9. If a low resolution is used,
fewer peaks will be observed, and separate peaks may merge
into a single peak which may affect apparent location. 12/8
Tr. a.m. (Myerson) 108:15-23. Typically, a resolution of 1
cm-1, 2 cm-1, or 4 cm-1 is used. 12/8
Tr. a.m. (Myerson) 109:12-19.
method used for identifying and locating peaks can also
introduce variability in the measured value. 12/9 Tr. p.m.
(Rogers) 41:3-6. Peak-picking software can use various
algorithms to determine whether something is a peak and the
location of the peak. 12/8 Tr. am. (Myerson) 106:15-20. Most
instruments come with a default setting for identifying peaks
and allow the user to adjust the settings to be more or less
sensitive. 12/8 Tr. a.m. (Myerson) 106:21-25. Peak-picking
software was available and in use as of 1995. 12/8 p.m. Tr.
order to reduce "noise, " or variability due to
factors other than the sample, a person of ordinary skill in
the art ("POSA") will typically run a number of
scans, and then "co-add" those scans, to increase
the signal to noise ratio. 12/8 p.m. Tr. (Myerson)
16:22-17:2. Typically, a POSA will perform 32 to 64 co-added
scans. 12/8 Tr. p.m. (Myerson) 60:19-24, 61:18-62:2.
the differences between peaks that a POSA would look for in
distinguishing between two different polymorphs of the same
compound are around 4 cm-1. 12/8 Tr. p.m.
(Myerson) 72:5-10. It is possible, though unlikely, however,
that a polymorph has an IR peak that is more than 18
cm-1 away from a corresponding peak in a different
polymorph of the same compound. 12/8 Tr. p.m. (Myerson)
72:23-73:4, 103:16-19. While IR spectroscopy can always be
used to distinguish between samples with different underlying
chemical structures, it cannot always be used to distinguish
between polymorphs. 12/8 Tr. p.m. (Myerson) 71:18-23.
Instead, there are many instances where IR spectroscopy
cannot distinguish between polymorphs. 12/8 Tr. p.m.
(Myerson) 72:1-4. Accordingly, while IR spectroscopy is
commonly used for identifying chemical species, it is only
occasionally used by itself to distinguish between different
crystalline forms. 12/8 Tr. p.m. (Myerson) 90:22-91:9; 12/9
Tr. am. (Rogers) 32:14-22.
are several additional methods by which crystalline forms may
be characterized. These include single crystal x-ray
diffraction, 12/8 Tr. a.m. (Myerson) 96:19-23, powder x-ray
diffraction ("XRPD"), 12/8 Tr. a.m. (Myerson)
96:24-97:4; 12/9 Tr. a.m. (Rogers) 32:14-21, and phase
transition analysis, such as by differential scanning
calorimetry ("DSC"), 12/8 Tr. a.m. (Myerson)
97:12-98:8; 12/9 Tr. am. (Rogers) 32:11-13. Each of these
methods was available to a POSA in 1997. 12/8 Tr. a.m.
(Myerson) 99:1-3; see 12/9 Tr. p.m. (Rogers) 53:11-13. Unlike
IR spectroscopy, XRPD will provide virtually conclusive
evidence informing a POSA what polymorph is being analyzed.
12/8 Tr. p.m. (Myerson) 70:20-23. Accordingly, IR
spectroscopy is not used nearly as often as XRPD to
distinguish between crystalline forms. See 12/8 Tr. p.m.
(Myerson) 70:18-72:4; 12/9 Tr. a.m. (Rogers) 32:14-22.
dysfunction refers to the dysfunction of a body's ability
to control its temperature. 12/12 Tr. a.m. (Locker) 84:6-11.
This typically occurs during menopause. 12/12 Tr. a.m.
(Locker) 84:8-11. The main symptoms associated with
thermoregulatory dysfunction are hot flashes or hot flushes
and night sweats. 12/12 Tr. a.m. (Locker) 84:12-13; 12/13 Tr.
(Simon) 119:2-8. Hot flashes, or thermoregulatory dysfunction
generally, may also be referred to as vasomotor symptoms.
12/12 Tr. a.m. (Locker) 89:21-23; 12/13 Tr. (Simon) 119:9-11.
The precise cause of vasomotor symptoms is unknown. 12/13 Tr.
(Simon) 121:17-19; 12/14 Tr. (Simon) 12:10-14. Sixty to
eighty percent of menopausal women experience vasomotor
symptoms, and approximately one in five seek medical
treatment for those symptoms. 12/13 Tr. (Simon) 119:16-22.
Background of the Claimed Inventions
Development of Crystalline Paroxetine Mesylate
late 1990s, researchers at Synthon developed a crystalline
form of paroxetine mesylate. See PTX-801.0003; JTX-1 at
7:45-60. Paroxetine mesylate is a salt in which the active
component is the paroxetine base. Dr. Benneker, a researcher
at Synthon, analyzed the crystalline form of paroxetine
mesylate that had been developed and generated a list of IR
peaks, the peaks now listed in claim 1 of the '271
patent. See PTX-801.0003.
spectrum used to identify the listed peaks was included in
the prosecution history of the '271 patent. The spectrum
had a resolution of 8 cm-1, rather than the
standard 1 cm-1 to 4 cm-1. 12/8 Tr.
a.m. (Myerson) 107:22-25, 109:12-19. At high transmission
areas, the spectrum appears to show a high degree of
variability in the signal due to factors other than the
sample, a problem that would often be addressed by co-adding
scans. 12/8 Tr. p.m. (Myerson) 16:5-17:2. The intrinsic
record does not appear to indicate how many co-added scans
Dr. Benneker performed. 12/8 Tr. p.m. (Myerson) 62:7-11.
the Interference Proceeding, Dr. Benneker submitted a
declaration describing how he measured the peaks from an IR
spectrum he had generated. PTX-801 ("Benneker
Declaration"); see also 12/8 Tr. p.m. (Myerson)
18:1-21:22. He did not use a peak-picking algorithm to
generate the list of claimed peaks in the '271 patent.
Instead, he measured the peaks by hand with a ruler. 12/8 Tr.
a.m. (Myerson) 107:17-21. Dr. Benneker stated that he
"calculated the wavenumber for each peak by measuring
with a ruler the distance between the wavenumbers marked on
the X-axis." PTX-801.0004. He further stated that
"[t]he measurements were made approximately to the
nearest 0.5 mm." PTX-0801.0004. The Benneker Declaration
further explained that he used these measurements to
calculate a scale factor. He then "placed the ruler
parallel to the Y-axis... directly against the side of the
peak to be measured and marked this point on the
X-axis." PTX-801.0004. Finally, he measured the distance
"approximately to the nearest 0.5 mm" from the
closest wavenumber marked on the X-axis to the marked point
on the X-axis and used this measurement to calculate the
peak's location. PTX-801.0004.
date, the crystalline form of paroxetine mesylate studied by
Dr. Benneker is the only polymorphic form that has been
found. 12/8 Tr. p.m. (Myerson) 9:21-10:3. In seeking to
institute the Interference Proceeding, Synthon affirmatively
represented to the PTO that "[a] 11 of the evidence...
indicates that there is only a single crystalline form of
paroxetine [mesylate]." JTX-6. Although it is
theoretically possible that another crystalline form of
paroxetine mesylate will be discovered in the future, 12/8
Tr. p.m. (Myerson) 10:17, Dr. Rogers testified that "it
is highly unlikely" that another form would be found.
12/9 Tr. a.m. (Rogers) 96:7-20. In reaching his conclusion,
Dr. Rogers considered the Genck Declaration and the Brittain
Declaration, which describe a polymorph screen in which Dr.
Genck attempted crystallization of paroxetine mesylate under
thousands of different sets of conditions. See 12/9 Tr. a.m.
89:24-91:20. Only one form was found and Dr. Genck concluded
that paroxetine mesylate was not polymorphic. 12/9 Tr. a.m.
Development of the Method of Treatment Patents
method of treatment patents claim uses of paroxetine to treat
vasomotor symptoms. The asserted claims of the '663
patent are directed to the use of the mesylate salt of
paroxetine, i.e., paroxetine mesylate, while the asserted
claims of the '251 patent are directed more generally to
any pharmaceutically acceptable salt of paroxetine.
Paroxetine belongs to a class of antidepressants known as
selective serotonin reuptake inhibitors ("SSRIs").
Paroxetine hydrochloride is a salt of paroxetine that has
been used commercially to treat depression since 1997, under
the name Paxil. 12/12 Tr. a.m. (Locker) 93:7-13.
symptoms have long been treated with hormone therapy. See,
e.g., 12/13 Tr. (Simon) 123:4-10. However, a large part of
the population of women needing treatment are unable to take
hormone therapy for vasomotor symptoms, including patients
who are suffering from or at risk of developing breast
cancer. 12/12 Tr. p.m. (Locker) 25:5-14; 12/13 Tr. (Simon)
123:11-22. Starting in the 1960s, researchers evaluated the
efficacy of various non-hormonal treatments. 12/13 Tr.
(Simon) 126:1-127:17. In the 1990s, researchers were
assessing the use of a variety of antidepressants for the
treatment of vasomotor symptoms, including venlafaxine (a
serotonin-norepinephrine reuptake inhibitor, or
"SNRI"), paroxetine, sertraline, fluoxetine,
citalopram, and mirtzapine. 12/13 Tr. (Simon) 127:20-134:20.
All of these agents were being tested at the antidepressant
dose or higher. 12/13 Tr. (Simon) 135:6-9. An additional
compound, gabapentin, also indicated efficacy during this
period. 12/13 Tr. (Simon) 136:21-137:5.
2000, a pilot study published by Stearns, et al., established
that paroxetine hydrochloride was effective to treat hot
flashes at doses as low as 10 mg/day. See 12/12 Tr. a.m.
(Locker) 90:9-18, 94:7-25; JTX-33). In 2004, a patent
application filed by Lemmens, et al, concluded that
paroxetine mesylate was preferable to paroxetine
hydrochloride as it is more highly water soluble and has
better thermal stability. 12/12 Tr. a.m. (Locker) 93:17-23;
PTX-983. In 2005, a more sophisticated study was published on
10 mg and 20 mg doses of paroxetine. 12/12 Tr. a.m. (Locker)
95:14; JTX-34. The second study also indicated that there was
a decrease in negative side effects from the 20 mg dose to
the 10 mg dose. 12/12 Tr. a.m. (Locker) 97:21-98:5. By 2005,
doctors were prescribing 10 mg doses of Paxil off-label for
treatment of hot flashes, 12/12 Tr. a.m. (Locker) 98:19-99:7,
and doctors were using other SSRIs and SNRIs to treat hot
flashes. 12/12 Tr. a.m. (Locker) 97:15-20.
2002, the Women's Health Initiative ("WHI")
study was published. This was a major study that clearly
demonstrated increased risk of several serious conditions,
including breast cancer, stroke and heart attacks, as a
result of hormonal treatments. 12/13 Tr. (Simon)
124:24-125:6. This led to an increased focus on developing
non-hormonal treatments for vasomotor symptoms. 12/13 Tr.
(Simon) 125:16-20. However, SSRIs and SNRIs, and paroxetine
in particular, have a number of side effects associated with
them, including weight gain and sexual dysfunction, which are
particularly problematic for menopausal women. 12/12 Tr. p.m.
(Locker) 30:16-31:21; 12/13 Tr. (Simon) 141:22-143:4.
Furthermore, at the time of the invention, tamoxifen was a
commonly prescribed breast cancer therapy, 12/12 Tr. p.m.
(Locker) 25:19-26:4; 12/13 Tr. (Simon) 144:1-16, and
paroxetine was known to interfere with the efficacy of
tamoxifen. 12/12 Tr. p.m. (Locker) 26:5-20; 12/13 Tr. (Simon)
Richards, the named inventor on the method of treatment
patents, testified that she had experience prescribing low
doses of antidepressants to treat pain, Richards Dep.
53:11-16, 53:20-54:6, knowledge that there is
thermoregulatory function in the hypothalamus, and knowledge
that there are serotonergic neurons in the hypothalamus.
Richards Dep. 57:1-58:13. Based on this, she ...