United States District Court, D. New Jersey
MEMORANDUM AN DORDER
G. SHERIDAN, U.S.D.J.
a patent infringement action brought by Merck Sharp &
Dohme Corp. (“Merck” or “Plaintiffs”)
against Actavis Laboratories FL, Inc., Andrx Corporation,
Actavis Pharma, Inc. and Actavis, Inc. (collectively,
“Actavis” or “Defendants”) for filing
an Abbreviated New Drug Application (“ANDA”) with
the Food & Drug Administration (“FDA”),
pursuant to 21 U.S.C. § 355(b)(2), for approval to
engage in the commercial manufacture, use or sale of a
generic version of Merck's Noxafil®
(posaconazole). See 35 U.S.C. § 271(e)(2).
listed the U.S. Patent No. 5, 661, 151 (“the '151
patent”) with the FDA's Approved Drug Products with
Therapeutic Equivalence Applications, commonly known as the
Orange Book, in order to market and sell a generic version of
Noxafil®. See 21 U.S.C. §
355(b)(1). The '151 patent is directed to the synthesis
and clinical use of the antifungal compound posaconazole,
which is used for treating or preventing fungal infections.
alleges that by filing the ANDA application with the FDA, and
in particular making a Paragraph IV certification with their
filing, Actavis had indicated that Merck's '151
patent is “invalid or will not be infringed by the
manufacture, use, or sale of [Actavis'] new drug for
which the application is submitted.” See 21
U.S.C. § 355(j)(2)(A)(vii)(IV).
pursuant to 21 U.S.C. § 355(j)(5)(B)(iii), Merck
initiated this suit against Actavis because Actavis'
request to market the generic version of
Noxafil® is prior to the expiration of the
action, a seven-day bench trial was held in July 2017. During
trial, Actavis set forth the defense that filing of the ANDA
application does not infringe the '151 patent because the
asserted claims 11 and 12 of the '151 patent are invalid.
In particular, Actavis asserted that-(i) claim 11 of the
'151 patent is invalid because it is inherently
anticipated by the European Patent Application EP 0 539 938
A1 (“EP '938”); and (ii) claim 12 is invalid
because it is obvious to a person of ordinary skill in the
art (“POSA”) in view of the EP '938
contrast, Merck argued that claims 11 and 12 of the '151
patent are valid because Actavis has not shown by a clear and
convincing evidence that the asserted claims are rendered
inherently anticipated or inherently obvious in view of the
EP '938 reference. Further, Merck argued that the EP
'938 reference is not a prior art reference under 35
U.S.C. §§ 102(a) and 103(a) because the inventive
concepts recited in claims 11 and 12 of the '151 patent
were invented on April 14, 1993, and diligently reduced to
practice prior to or soon thereafter. As such, antedating the
EP '938 reference, published on May 5, 1993.
arguably asserted that claim 12 is invalid because it is
inherently anticipated by the EP '938 reference; however,
the parties later stipulated that claim 12 is not inherently
anticipated by the EP '938 reference. (See D.I.
careful review and consideration of the evidence presented at
the bench trial, the Court finds that Merck has provided that
the subject matter recited in claims 11 and 12 of the
'151 patent was conceived on April 14, 1993, which was
diligently reduced to practice thereafter. Thereby, rendering
the EP '938 reference not a prior art reference to the
'151 patent. As such, the Court finds that claim 11 of
the '151 patent is not invalid under 35 U.S.C. §
102(a); and claim 12 of the '151 patent is not invalid
under 35 U.S.C. § 103(a).
know the Leahy-Smith America Invents Act (“AIA”)
substantially changed the patent law on September 16, 2011.
One such change amended the prior law from a ‘first to
invent' to ‘first to file' system except in
certain cases. The AIA further provided that the amendments
set forth in the AIA would not take effect until eighteen
(18) months after enactment (March 16, 2013). This matter
arises prior to the effective date. As such, the pre-existing
law applies. (See Manual of Patent Examining
Procedure (“MPEP”), Section 2159.01); also
see AIA 125 Stat. at *293 (Sec. 3(n)(1)).
patent application of the '151 patent was filed on June
2, 1995, which later issued on August 26, 1997, to Schering
Corporation (“Schering”). On August 30, 2012,
Schering assigned its rights in the '151 patent to
Merck. The '151 patent was listed in the
FDA's Orange Book in three different New Drug
Applications (“NDA”), which are directed to an
intravenous infusion solution (300MG/16.7ML (18MG/ML)); oral
suspension (40MG/ML); and oral tablet with delayed release
(100MG). The NDA, N205053, for the oral tablet with delayed
release (100MG), is the one that Actavis seeks approval from
the FDA to market and sell a generic version in the United
States. (See Complaint (“Compl.”) at
¶ 19; D.I. 1).On November 25, 2013, the FDA approved
Merck's NDA N205053, directed to oral tablet with delayed
release (100MG), for use in “prophylaxis of invasive
aspergillus and candida infections.”
ANDA filing with the FDA, Actavis included a written
certification (¶ IV Certification) alleging that the
claims of the '151 patent are invalid or otherwise will
not be infringed by Actavis' ANDA product. (See
id at ¶ 20; see also 21 U.S.C. §
on August 6, 2015, Merck initiated this suit against Actavis;
alleging that Actavis' request to market the generic
version of Noxafil® is prior to the expiration
of the '151 patent. As such, infringing Merck's
intellectual property rights granted under the '151
patent. (See Id. at ¶¶ 26-30; see
also 35 U.S.C. § 271(e)(2)).
asserted claims 11 and 12 of the '151 patent against
Actavis in this suit. (See First Amended Invalidity
Contentions at 5; D.I. 67). Independent claim 11 being
directed to the compound posaconazole, and dependent claim 12
being directed to a pharmaceutical composition comprising the
posaconazole of claim 11 and a pharmaceutically acceptable
carrier. Claim 12 depends from claim 11. (Id. at 6).
In its invalidity contentions, Actavis asserted, inter
alia, that claims 11 and 12 of the '151 patent are
invalid because-(i) claim 11 is inherently anticipated by the
EP '938 reference (see id at 21); (ii) claim 12
is inherently anticipated by the EP '938 reference
(see id at 23); (iii) claim 11 is obvious in view of
multiple grounds (see id at 23-34); and (iv) claim
12 is obvious in view of the EP '938 reference (see
trial, Actavis bearing the burden to invalidate the asserted
claims of the '151 patent, presented mainly expert
evidence to show that the asserted claims 11 and 12 of the
'151 patent as being invalid as noted above. The experts
were-Dr. Paul Ortiz De Montellano; Dr. Stanley Roberts; Dr.
Wei Lu; Dr. Gary Glick; Dr. Edwin P. Alyea; and portions of
videotaped depositions of Dr. Viyoor M. Girijavallabhan
(“Dr. Giri”), Dr. Frank Bennett, and Mr. Frank
other hand, Merck defended the '151 patent by arguing
that the asserted claims 11 and 12 are not inherently
anticipated or rendered obvious in view of the EP '938
reference. Further, Merck argued that the EP '938
reference does not qualify as a prior art reference because
the posaconazole compound recited in claim 11 and the
pharmaceutical composition recited in claim 12 were conceived
before the publication date of the EP '938 reference (May
5, 1993), and diligently reduced to practice soon thereafter.
In order to advance these positions, Merck relied on the
following witnesses and experts-Dr. Birendra N. Pramanik; Dr.
Anil Saksena; Dr. Roland Dolle; Dr. Fredrick P. Guengerich;
Dr. Mahmoud Ghannoum; Dr. Kieren Marr; Dr. Giri; Dr. Raymond
Lovey; and Dr. Frank Bennett.
end of the trial, the parties submitted proposed findings of
fact and conclusions of law, followed by reply papers.
(See Pl.'s Findings of Fact (“FoF”),
D.I. 200; Def.'s FoF, D.I. 201; Def.'s Conclusions of
Law (“CoL”), D.I. 204; Pl.'s CoL, D.I. 205;
Def.'s Reply, D.I. 208; Pl.'s Reply, D.I. 209).
issues litigated before the Court were whether-(1) Merck can
antedate the EP '938 reference by showing that the
claimed subject matter of claims 11 and 12 were conceived
before the publication date of the EP '938 reference, and
diligently reduced to practice soon thereafter; and (2) if
the EP '938 reference is a prior art reference to the
'151 patent, is claim 11 inherently anticipated by the EP
'938 reference under the pre-law; and (3) if the EP
'938 reference is prior art, is claim 12 rendered obvious
under the pre-law. (See Def.'s FoF at ¶ 3;
see also Pl.'s FoF at ¶ 16).
Conventional Technology & Drug
around 1993 (the time of the inventive concepts disclosed in
the '151 patent) there was a need for broad-spectrum
antifungal agents with increased solubility and favorable
activity profile for treating systemic fungal infections. In
particular, systemic fungal infections such as, Aspergillus,
Candida, Cryptococcus and opportunistic infections, needed to
be treated. (See the '151 patent, col. 2, ll.
the early 1990s, when the HIV/AIDS disease was very high, and
there were many immune-suppressed patients, medical
professionals in this field were aware of the need to cure or
treat fungal infections more effectively. (See
Plaintiff's Expert, Dr. Kieren Marr's testimony
Transcript (“Trans.”) at 1185:19-24,
1195:21-1196:10 (Marr), dated July 19, 2017). Dr. Marr
testified that there are two types of fungal infections-local
and systemic functions. Distinguishing between them, she
stated that a local fungal infection, such as athlete's
foot is limited to an external part of the body; but
systematic fungal infections involve fungal invasion of more
than one organ system, such as the blood, lungs, or brain,
which are caused by yeasts and molds such as Aspergillus,
Candida, Zygomycetes, Cryptococus, and Coccidioides. Systemic
fungal infections being prevalent in persons who have
compromised immune systems. (See Trans. at 1191:22-
1194:10 (Marr); see also Pl.'s FoF at
Marr, “an expert in infection diseases, particularly
the pathogenesis, diagnosis and prevention and treatment of
fungal infections” (see Trans. at 1188:3-6),
testified that one of the drugs available to physicians in
the year 1993 to treat people with fungal infections was
Amphotericin B, which was administered intravenously. The
side effect of this drug was that it caused severe kidney
destruction; resulting in fevers and chills. (See
Trans. at 1194:16-25 (Marr); see also Pl's FoF
at ¶¶ 79, 81).
Dr. Marr noted that the other conventional drugs
included-Flucytosine, Ketoconazole, Fluconazole, and
Itraconazole. (See PX 1057). Dr. Marr testified that
in 1993, the only antifungal drugs available for physicians
to prescribe for systemic fungal infections were the
aforementioned drugs. (See Trans. at 1202:3-7). All
of these conventional drugs have a broader spectrum than
their predecessor, but they have significant side effects.
For example, Flucytosine had limited usage because fungal
infections became rapidly resistant to this drug
(see Trans. at 1196:20-23); Ketoconazole, approved
by the FDA in 1981, created toxicities in the liver when it
interacted with the P450 enzyme (see Trans. at
1197:1-6; see also Pl.'s FoF at ¶¶ 83,
84); Fluconazole, which was considered very safe, had
activity against Candida species, but had no activity against
molds (i.e., Zygomycetes) (see Trans. at
1198:19-1199:3, 1200:9-10); and lastly, Itraconazole,
approved by the FDA in 1992, was effective against molds
(Aspergillus); but Itraconazole was not very effective in
treating people with suppressed immune systems, and was not
safe for patients with heart defects. (See Trans. at
1200:11-25; see also Pl.'s FoF at ¶ 86).
Dr. Marr testified that in the late 1980s and the early
‘90s there were no FDA approved drugs available to
prevent or treat patients that were susceptible to fungal
infections, there was only conventional amphotericin B.
(See Trans. 1203:24-1204:1). As such, there was a
pressing need for a broad spectrum drug that could be
administered for preventive use for diabetic patients, AIDS
patients and transplant patients. (See Pl.'s FoF
at ¶ 88).
Dr. Dolle, Merck's expert in drug discovery and medicinal
chemistry (see Trans. at 538:18-21), concurred with
Dr. Marr about the ongoing need for antifungal drugs. In
1940s, Benzimidazole, a forerunner of azole class, was
introduced in the market, which had weak activity against
fungi. (See PX 1017). Then in the 1960s, Miconazole,
a topical agent to treat things like fungus and ringworm, was
approved by the FDA around 1960s. Thereafter, in 1977,
Ketoconazole was approved, which was the first oral active
agent. (See Trans. at 727:12-25 (Dolle)).
Ketoconazole, the first orally active compound, lead further
interest by the scientific community into following up on
azoles in treating antifungal infections. (Id. at
Dolle further noted that developing a new antifungal drug is
a long drawn out process. (See PX 1002). He
explained that the pre-clinical phase a lead compound is
identified, optimized, and then tested in animals. Whereas,
under the clinical phase, the lead compound is tested in
humans; and the assessment of the lead compound's
efficacy and safety in humans is determined, before being
approved by the FDA. (See Trans. at 541:25-542:1-7
summary, Dr. Dolle noted that it is an industry average that
around 10, 000 compounds that are synthesized or evaluated
for their biological activity under the pre-clinical phase.
Only 0.1% percent of those compounds enter the clinical
phase, out of which only 10% have a chance of getting FDA
approval. (See Trans. at 542:8-23 (Dolle)).
Consequently, the entire process may exceed ten (10) years
from possessing a lead compound through the clinical phase
and obtaining FDA approval. (See Trans. 542:21-543:3
Development Of Posaconazole
early 1993, Schering performed studies on Compound IIc (i.e.,
SCH-51048). The research and studies indicated that when
Compound IIc was administered to mice, there was a compound
within mice's blood that had better antifungal activity
than its parent compound (Compound IIc). This suggested to
the scientists at Schering, in particular Dr. Saksena, that
some metabolite of Compound IIc was more active than the
parent compound itself. (See Pl.'s FoF at ¶
108; citing Trans. at 472:4-19; 1353:16-19; JX
44.0027; JX 44.0036). This active metabolite was called
Dr. Saksena learned about the existence of this active
metabolite, Metabolite A, he did not have any idea or mental
conception of the structure of this active metabolite.
(See Pl.'s FoF at ¶ 114). As such, Dr.
Saksena and his colleagues attempted to learn more about the
structure of this metabolite by undertaking further research.
(Id. at ¶ 117). On April 13 and 14, 1993, Dr.
Larry Heimark, a mass spectrometrist, performed serum samples
of the antifungally active CF-1 mouse metabolite of Compound
IIc. (Id. at ¶ 118; citing JX
7.0003-05). Dr. Birendra Pramanik, a senior mass
spectrometrist and Dr. Heimark's supervisor, analyzed the
mass spectra provided by Dr. Heimark and wrote down the
results of his analysis in his lab notebook. (Id. at
¶¶ 119-120). These results are shown below-
(See JX 7.0001). Dr. Pramanik's handwritten
remarks (above) are difficult to read but in substance the
notes state that this structure, as labeled as “SCH
51048 Metabolite, ” is-(i) data of the metabolite
sample indicated that the compound is a secondary alcohol;
(ii) oxidation occurred at the side chain (X) (annotated in
the figure); and (iii) additional work is in progress.
same day, April 14, 1993, Dr. Pramanik discussed his findings
and mass spectra with Drs. Saksena and Giri. Based on the
evidence before them, Drs. Pramanik, Saksena and Giri
perceived that Metabolite A could have any of seven possible
structures. These seven possibilities included-two primary
alcohols, four secondary alcohols, and one tertiary alcohol.
(See Pl.'s FoF at ¶¶ 121-124).
“Primary” and “secondary” refer to
the specific carbon to which the OH group is attached.
(See Def.'s Br. at 4). The tertiary alcohol was
quickly ruled out during this meeting, and on April 14, 1993,
they decided to synthesize and test each of the six alcohols
to determine which one of the six alcohols had antifungal
activity. (See Pl.'s FoF at ¶ 127;
citing Trans. at 476:13-20 (Saksena); 1145:21-1146:2
(Giri); and 1337:25-1338:2 (Glick)).
alcohols were synthesized as three pairs of racemates (i.e.,
as three mixtures, each containing a pair of two distinct
stereoisomers) for purposes of synthetic convenience, as the
three racemates could be more quickly prepared; resulting in
an early evaluation of the biological activity of the
compounds. (See Pl.'s FoF at ¶¶
posaconazole and SCH-51048 are each single
“stereoisomers.” In a general sense, this means
that each compound has a corresponding pair compound that has
the same atoms, attached in the same way, but with a
non-superimposable mirror-image configuration in
three-dimensional space, similar to left and right hands.
(See Trans. at 60:11-61:17; 62:23-63:23) (Ortiz De
Montellano). These mirror-image compounds are denoted as
“(R)” and “(S)”
forms of the compound. (See Trans. at 62:20-22;
63:24-64:3) (Ortiz De Montellano). The different
stereoisomers of a molecule often have different biological
activity and/or toxicity. One well-known example of this
phenomenon is the drug thalidomide. The (R) form of
thalidomide is effective against morning sickness, while the
(S) form causes birth defects. (See Trans.
at 64:23-65:11) (Ortiz De Montellano). See
Def.'s FoF at ¶¶ 11-12.
purpose of synthesizing the six alcohols was to test their
activity against fungal agents, both in vivo and
in vitro, and ultimately determine if any of these
compounds could be developed into marketable drugs.
(Id. at ¶ 132). To test each of the six
alcohols in vivo, each of them would have to be
formulated as a pharmaceutical composition containing a
potentially antifungally effective amount of posaconazole
suitable for administration to laboratory animals suffering
from fungal infections. (Id. at ¶ 133).
synthesis of the six alcohols, which were determined during
the April 14, 1993, meeting between Dr. Giri, Dr. Saksena and
Dr. Pramanik, was assigned to Mr. Raymond Lovey. (Def.'s
FoF at ¶ 25). Mr. Lovey was tasked to synthesize three
racemic mixture, or racemate, (mixtures of two
stereoisomers), SCH-55801, SCH-55803, and SCH55805.
(Id. at ¶ 26; Pl.'s FoF at ¶ 148). The
three pairs of the racemic mixtures are shown below-
(See Pl.'s FoF at ¶ 180). SCH-55801 and
SCH-55803 corresponded to the four secondary alcohols of
SCH-51048, and SCH-55805 corresponded to the two primary
alcohols of SCH-51048. (Id. at ¶ 181).
the April 14, 1993 meeting, Drs. Giri and Saksena provided
Mr. Lovey with an outline of the synthetic steps to make the
racemates. (See Pl.'s FoF at ¶ 150). Mr.
Lovey's five-step synthesis of SCH-55801 started on April
26, 1993 and was completed by May 26, 1993. (Id. at
¶ 154). The five-steps included-(i) dihydroxylation of
2-pentene (step 1); (ii) protection of 2, 3-pentanediol (step
2); (iii) sulfonation of SEM protected 2, 3 pentanediol (step
3); (iv) coupling of triazole core (step 4); and (v)
deprotection to remove SEM protecting group, yielding
posaconazole and its enantiomer (step 5). (See PX
1010; Pl.'s FoF at ¶ 182-183).
26, 1993, Mr. Lovey made SCH 55801, posaconazole, as a
one-to-one mixture with the R, R isomer. (See
Pl.'s FoF at ¶¶ 184-185). A mass spectra
analysis done on June 14, 1993 indicated SCH-55801 had the
distinctive fragmentation pattern of the secondary alcohol
analogs of SCH-51048. (Id. at ¶ 187). The three
racemic mixtures Mr. Lovey synthesized were tested in in
vitro experiments, which showed that all had activity
and that they were more active than SCH-51048. (Id.
at ¶ 190).
the three racemic mixtures-SCH-55801, SCH-55803 and
SCH-55805-were tested for in vitro antifungal
activity, Drs. Giri and Saksena directed their team to make
the six alcohols in pure form. (Id. at ¶ 197).
Dr. Bennett, one of the Schering scientists tasked with
making the pure form, began his work on June 30, 1993, and
concluded the synthesis of pure posaconazole on August 20,
1993. (Id. at ¶ 200). Dr. Bennett began with
synthetic routes to the azole core and the piperazine linker
‘in hand, ' and attached the side chain necessary
to make posaconazole as a pure compound. (Id. at
¶¶ 159-160). As such, Dr. Bennett was the first
person to make SCH-56592, which was later known as
posaconazole, not in a mixture with its RR enantimoer.
(Id. at ¶ 199). The in vivo testing
showed that SCH 56592 (posaconazole) had the best oral
activity, the best pharmacokinetics, and the best efficacy of
the six individual stereoisomers. (Id. at ¶
October 18, 1993, a protocol for testing all six secondary
and primary alcohol analogs of SCH-51048, including
posaconazole, in mice infected with Candida albicans
was in place; and testing of the six alcohols as
pharmaceuticals began. (Id. at ¶ 209). Between
October 18, 1993 and December 21, 1993, posaconazole was
tested in vivo, the results were analyzed, and 171,
083 patent application (“'083 patent
application”) was filed. (Id. at ¶ 211).
The '151 Patent
Earliest Priority Date
parties agree that the earliest priority date of the '151
patent is December 21, 1993. (See First Amended
Invalidity Contentions at 6). The '151 patent is a
continuation-in-part (“CIP”)application of a
PCT application, and the PCT application is a CIP application
of the '083 patent application (“'083 patent
Disclosure of the '151 Patent
'151 patent is generally directed to the synthesis and
clinical use of antifungal compound posaconazole, which is
used for treating and/or preventing fungal infections.
(See Abstract of the '151 patent). Posaconazole
is an azole antifungal, which means it is a particular class
of chemical compounds that are known to have antifungal
activity. (See Trans. at 7:8-14). The '151
patent discloses antifungal compounds of formula I and
pharmaceutical compositions, which are expected to exhibit
anti-allergic, anti-inflammatory and immunomodulating
activities. The pharmaceutical composition contains a
fungicidally effective amount of other antifungal compounds.
(Id. at col. 56, ll. 40-67).
chemical structure of posaconazole, which shows the
arrangement of the atoms within the molecules and which atoms
are bonded together, and whether single, double or triple
bonds are formed between, is illustrated in claim 11-
(see the '151 patent, col. 78, ll. 1-20; see
also Def.'s Br. at 2; D.I. 162; see also
Def.'s FoF at ¶ 9 (“there are three parts to
the posaconazole structure, the azole core, the piperazine
linker and the side chain.”); see also
Pl.'s FoF at ¶ 134). Dr. Dolle, Merck's expert,
testified that the chemical structure of the posaconazole
compound is a three-dimensional structure, wherein the dashed
lines and the bold solid lines, as illustrated above,
represent groups behind the plane and coming out of the
plane, respectively. (See Trans. 563:24-564:3
'151 patent further discloses that pharmaceutical
compositions are formulated by combining the compound of
formula I or an equivalent amount of a pharmaceutically
acceptable salt of compound I with a suitable,
inert, pharmaceutically acceptable carrier or diluent.
Examples of suitable pharmaceutical compositions include
solid or liquid compositions for oral administration such as
tablets, capsules, pills, powders, granules, solutions,
suppositories, troches, lozenges, suspensions or emulsions.
(Id. at col. 57, ll. 40-50).
the '151 patent discloses that a solid carrier can be one
or more substances which may act as diluents, flavoring
agents, solubilizers, lubricants, suspending agents, binders
or tablet disintegrating agents, or as an encapsulating
material. The carrier can also be a finely divided solid
which is in admixture with the finely divided active
compound. In a tablet form, for example, the active compound
is mixed with the carrier that has the necessary binding
properties. The carrier is added in suitable proportions such
that the tablet is compacted in the desired shape and size.
(Id. at col. 57, ll. 45-55).
prosecution of the patent application of the '151 patent,
the examiner rejected the claimed subject matter. The
Applicant amended the then pending claims to include claim
term “in vivo” to differentiate over the cited
art. (See Image File Wrapper of the '151 patent,
Applicant's Arguments/Remarks Made in an Amendment, filed
May 24, 1996). This amendment was made in response to patent
examiner's rejection mailed on November 22, 1995.
Additionally, arguments against the obviousness rejection
under 35 U.S.C. § 103 were also made. (Id.)
mailing a final rejection on August 21, 1996, the examiner
conducted a personal interview with the Applicant's
representative. During the personal interview, the enablement
rejection under pre-AIA 35 U.S.C. § 112, first
paragraph, was discussed, and the Applicants agreed to
provide an affidavit demonstrating that enablement exists for
use of “in vivo” esters. (See Examiner
Interview Summary Record mailed on December 19, 1996).
the Applicant filed a response to the outstanding Office
action with a declaration from Dr. Ashit K. Ganguly, a
co-inventor of the '151 patent. In the response, the
Applicant essentially argued that based on the specification
a POSA would be able to readily determine which of the ester
compounds would be soluble or suspendible in a
pharmaceutically acceptable aqueous media. (See
Applicant's Arguments/Remarks filed on January 29, 1997;
citing Declaration of Dr. Ganguly at ¶ 17).
Applicants noted that they are “amending claim 17 of
this application to cover a preferred embodiment, and to
recite that such esters of the compounds of the claimed
invention have a solubility in a pharmaceutically acceptable
media of at least about 1 to about 50 mg/ml.”
(Id. at 6). Thereafter, on February 7, 1997, a
notice of allowance was mailed by the patent examiner, which
was later followed by a corrected notice of allowance on