It's time to say goodbye to 2020 & also this blog. As most of the you are aware that "Pharma IP Circle" has moved to new address & this current address would no longer serve. Looking forward to 2021 with new learning & experience.
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On Dec. 21, 2020, Federal Circuit affirmed district court’s
summary judgment that found infringement under Doctrine of Equivalents (DoE).
Eli Lilly owns US 7,772,209 patent which relates to “a
method of administering an antifolate to a mammal in need thereof, comprising
administering an effective amount of said antifolate in combination with a
methylmalonic acid lowering agent”. Independent claims covers administration of
pemetrexed disodium (antifolate) with folic acid & methylmalonic acid
lowering agent (vitamin B12). This patent is listed in Orange Book for the
product ALIMTA®. Eli Lilly markets
ALIMTA in USA for the treatment of mesothelioma and certain types of lung
cancer. Apotex filed NDA with USFDA to
market different salt i.e. pemetrexed dipotassium. Eli Lilly then sued Apotex for infringement. United
States District Court for the Southern District of Indiana issued summary
judgment of infringement in favour of Lilly. It found that Lilly is not
estopped from arguing DoE because there was no Prosecution History Estoppel
(PHE).
Apotex argued that the term “ALIMTA” in the original claims
would have been understood to mean “pemetrexed,” therefore, Lilly’s amendment
to replace “ALIMTA” with “pemetrexed disodium” was a narrowing amendment and
Lilly surrendered all other salt forms of pemetrexed. Federal Circuit, however,
sided with district court & said that this amendment was not narrowing one.
The intrinsic record equates ALIMTA with pemetrexed disodium. The specification
refers to “pemetrexed disodium” twice, both times in association with ALIMTA. Moreover,
the prosecution history confirms that the inventors used “ALIMTA” in the
original claims—and the Examiner understood the term—as Lilly’s trade name for pemetrexed
disodium. Examiner rejected claims related to ALIMTA trademark under 35 U.S.C.
112, second paragraph because it is improper to use trademark in the claims
according to MPEP. In response to the rejection, Lilly canceled its claims
reciting the trade name and pursued claims using the generic name (pemetrexed
disodium), which mooted the rejection.Therefore, nothing in the prosecution
history suggests that Lilly’s amendment narrowed the claims or or that either
Lilly or the Examiner understood “ALIMTA” to mean anything other than
pemetrexed disodium.
Thus, the district court properly concluded that prosecution
history estoppel does not bar Lilly’s infringement claims under the doctrine of
equivalents.
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Mahendra Gunjal
On Dec. 18, 2020, Federal Circuit affirmed (Rule 36
judgment) Delaware court in Uceris® litigation.
Previously,
Plaintiffs Bausch Health Americas, Inc., Salix Pharmaceuticals Ltd., and Cosmo
Technologies Limited (collectively, "Plaintiffs") filed complaint
asserting that Defendants Actavis Laboratories FL., Inc., Actavis Pharma, Inc.,
Teva Pharmaceuticals USA, Inc., and Teva Pharmaceutical Industries Ltd.
(collectively, "Defendants") infringed and continue to infringe U.S.
Patent Nos. 10,052,286, 10,064,878, 10,105,374, 10,143,698, 10,154,964, and 10,172,799
by filing ANDA for budesonide extended release tablets, 9 mg. On Oct 28, 2019,
Delaware court issued final order & judgment finding of noninfringement in
favor of Defendants.
On Dec. 16, 2020, Federal Circuit affirmed (Rule 36
judgment) PTAB finding method of use patent invalid as obvious.You can find the
IPR details reported “"here"” on this blog.
IPR decision: Dec. 08, 2020
|
AIA Review # |
Filing Date |
Institution Date |
Petitioner |
Patent |
Respondent |
Status |
|
IPR2020-01045 |
06/10/2020 |
09/01/2020 |
Teva |
7,326,708 |
Merck |
Terminated-Settled |
Note: Mylan already filed IPR on US’708 patent on 10/30/2019 and PTAB instituted IPR on 05/12/2020. DRL & Sun also filed IPRs (IPR2020-01060 & IPR2020-01072) which were instituted on 09/01/2020.
US 7,326,708 (Merck & Co.; Exp: 05/24/2027 with
PED):
1. A dihydrogenphosphate salt of
4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine
of structural formula I:##STR## or a hydrate thereof.
On Dec. 04, 2020, UK High Court found second medical use
patent valid & infringed by Mylan.
Neurim holds EP 1,441,702 patent, which is related to use of
melatonin in improving the restorative quality of sleep, in a patient suffering
from primary insomnia. Mylan/Generics UK
plans to bring generic version of drug in the market. The issues before court
concerned the invalidity of patent as Mylan admitted infringement if patent is
found valid. Mylan asserted that claims of patent are invalid under lack of
novelty, lack of inventive step & insufficiency. Claims 1
and 4 were of relevance here:
1.
Use of a prolonged release formulation comprising melatonin in unit dosage form comprising 2 mg of
melatonin, in the manufacture of a medicament for improving the restorative
quality of sleep in a patient aged 55 years or older suffering
from primary insomnia characterized
by non-restorative
sleep, wherein the medicament comprises also at least one pharmaceutically
acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers,
adjuvant or carrier.
4.
A medicament for use in improving the restorative quality of sleep in a
patient aged 55 year or older suffering from primary insomnia characterized by non-restorative
sleep, which comprises a prolonged release formulation comprising melatonin in
unit dosage form, comprising 2 mg of melatonin, and at least one pharmaceutically
acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers,
adjuvant or carrier.
Mylan cited various prior arts among which “Haimov 1995” was closest one. It disclosed effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs by administering 2 mg sustained-release melatonin. With respect to novelty, Court held that Haimov in no way anticipates the patent because study was directed to a completely different matter. The focus was on “melatonin-deficient” individuals, because the aim of the study was to see if the curing of such a deficiency would improve sleep. There was certainly no focus on restorative sleep or quality of sleep in the technical sense as claimed in patent. Court thus concluded that Skilled Person would have learned nothing about the effect of melatonin on Primary Insomnia characterized by non-restorative sleep from Haimov.
With respect to inventive step, Mylan combined this reference with
another references such as “MELATONEX label
and Zisapel”. MELATONEX is a dietary supplement containing melatonin which is
sold in USA without prescription. MELATONEX supplementation can help to restore
the melatonin for a restful, natural sleep. Zisapel is a review of the
literature in the area of melatonin treatment. It neither reported any original
research nor did it give any meta-analysis of the data reviewed. Court said
that Zisapel goes nowhere close to exploring any relationship
between non-restorative sleep in Primary Insomniacs and melatonin. There is
nothing to render the invention in the patent obvious to the Skilled Person.
With respect to insufficiency also, Court did not convince with Mylan’s argument. Mylan contended that there was no data in the patent which evidenced the claimed effect, namely an improvement in the restorative quality of sleep in a patient suffering from Primary Insomnia characterized by non-restorative sleep. Court focused on Examples 2 and 3 and considered whether they render the patent plausible. Court said that these examples disclose reasonably large clinical study in patients who were Primary Insomniacs at least some of whose sleep was characterized by its non-restorative quality. These studies were conducted on established lines and resulted in a statistically significant outcome in that it enabled the conclusion that melatonin enhanced the restorative value of sleep. Thus Court rejected the contention that the patent is invalid by reason of insufficiency.
On Nov. 30, 2020, Delaware court on remand found Quillivant
XR® patents valid & infringed by ANDA filer in a Hatch-Waxman suit.
Plaintiff (Tris Pharma) filed suit against defendant (Actavis)
for alleged infringement of U.S. Patent Nos. 8,465,765; 8,563,033; 8,778,390;
8,956,649 and 9,040,083. Actavis challenged the validity based on obviousness
and obviousness-type double patenting. After a five-day bench trial, the
original judge (now retired) found all the asserted claims to be invalid for
obviousness under 3 5 U.S. C. § 103. Tris appealed. The Federal Circuit vacated
the judgment because [the judge]'s obviousness decision lacked the requisite
fact-finding, and because the [judge] erred in rejecting Tris's evidence of
objective indicia of non-obviousness." The Federal Circuit thus remanded
the obviousness analysis to the district court for further fact-finding.
All asserted claims basically related to methylphenidate
aqueous extended release oral suspension & its pharmacokinetic (PK) &
pharmacodynamic (PD) aspects. Federal Circuit specifically ordered further
fact-finding to address whether a liquid MPH formulation with a single mean
PK profile, 12-hour duration of effect, 45-minute onset of action,
Tmax range of 4 to 5.25 hours would have been obvious over the prior art.
Prior arts cited were disclosing one or more limitations but not all. Most of
the prior arts were related to ER solid formulations of methylphenidate. Only
one art cited was related to liquid formulation but that disclosed IR
composition. The question on remand was whether Actavis has demonstrated by
clear and convincing evidence that an artisan of ordinary skill would have been
motivated to achieve the combination in question and would have had a
reasonable expectation of success in doing so.
Court said that Actavis bears the burden & their arguments
are confusing and conflicting. Actavis first submitted that POSA would have
been motivated to make a formulation with a single peak profile. Court said
that assuming arguendo that this fact
were established, it would not by itself constitute clear and convincing evidence
that an artisan of ordinary skill would have been motivated to combine a single
peak profile with a liquid MPH formulation that has both a 12-hour duration and
45-minute onset. On the contrary, Actavis next states in the opening line of
its second argument that its own expert, Dr. Staller, established at trial
"that POSA would not have been concerned about the specific shape of the
PK curve-[because] clinical effects [i.e., PD characteristics as opposed to PK
characteristics] are what matter." Court thus said that, so POSA would
have been indifferent (i.e., would have lacked motivation) to use a formulation
that produced a single peak profile. Actavis' last affirmative argument with
respect to motivation to combine a single peak profile, 12-hour duration, and
45-minute onset in a liquid MPH formulation too, lacks merits. Actavis argued that
POSA "would have been motivated to pursue this [combination] because [the
combination had] already appeared in the prior art." Court however said that
only two of the extended release prior art references disclosed formulations
with a single mean peak plasma profile, and neither of those references
achieved an onset within 45 minutes. Court also said that there was no
reasonable expectation of success because prior art taught away from combining
in a liquid MPH formulation a single mean peak, 12-hour duration, and 45-minute
onset. Specifically, prior art taught that multiple peaks, achieved by multiple
pulses of medication, were required to achieve both a 12-hour duration and
45-minute onset. Thus, the prior art taught away from use of a single peak to
achieve that combination of clinical effects.
With respect to secondary consideration, court found unexpected
results and long-felt, unmet need in favor of Tris. Court said that combination
of single peak profile with a 12-hour duration and 45-minute onset was
unexpected as discussed above. Moreover, Tris's evidence of long-felt unmet
need as of July 2010 for a liquid methylphenidate formulation with a 12-hour
duration and 45-minute onset is especially compelling. Because, children, the
primary focus of ADHD treatment, often have difficulty swallowing pills; and it
is much easier for patients generally and children in particular to comply with
a therapy regimen that is accomplished with a single daily dose as opposed to
multiple doses taken throughout the day. The need was long-felt and unmet
because even though methylphenidate had been used to treat ADHD since the mid-1950s,
the only two formulations available as of July 2010 that allowed for a single daily
dose regimen (i.e., 12-hour duration of effect) and an early onset were Concerta®
and Focalin®, and both of those formulations required the swallowing of a pill
or capsule. The only liquid formulation available at the time, Methylin® OS, was
an immediate release product with a duration of effect that lasted only three
to four hours.
Court thus concluded that all asserted claims are not
invalid and defendants infringed each of the asserted claims.
On Nov. 30, 2020, Delaware court found composition patent covering
combination invalid as obvious & not infringing.
Background of the
case:
Plaintiffs (Horizon) owns NDA for DUEXIS® (ibuprofen and
famotidine) tablets, 800 mg / 26.6 mg. It is indicated for the relief of signs
and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the
risk of developing upper gastrointestinal ulcers in patients who are taking
ibuprofen for those indications. Defendant (Alkem) submitted ANDA on March 31,
2018 seeking USFDA approval to market generic version. Horizon sued Alkem in district
of Delaware for infringement of OB listed patents, such as U.S. Patent Nos.
8,309,127, 8,318,202, 8,449,910, 8,501,228 & 8,067,033. By trial the
parties narrowed the case to US’033 patent only.
The asserted patent is directed to stable pharmaceutical
compositions of famotidine and ibuprofen separated by way of barrier layer in a
single dosage form. Independent claim 1
is:
1. A pharmaceutical
composition comprising a first portion
that comprises 800 mg ibuprofen and a second
portion that comprises 26.6 mg famotidine, wherein the surface area of
direct physical contact between ibuprofen and famotidine does not exceed 130
mm2 , wherein no more than about 1% sulfamide is present when the
composition is stored at 40° C. and 75% relative humidity for a period of one
month, wherein the composition is formulated so that release of both the
ibuprofen and the famotidine occurs rapidly at about the same time, wherein
none of the composition, the famotidine, and the ibuprofen is enterically
coated or formulated for sustained or delayed release, and wherein the
composition is for use according to a TID (three times per day) administration
schedule for reducing 4 the risk of developing ibuprofen-induced ulcers in a
human patient requiring ibuprofen for an ibuprofen-responsive condition.
It was known that Ibuprofen (NSAID) causes ulceration when
used in the treatment. Therefore search was carried out to prevent this side
effects. Famotidine is a gastroprotectant which helps to reduce this side
effect. But both these two active ingredients are not compatible when used
together. Therefore, plaintiff come with the dosage form where these two actives
are separated, such as tablet in tablet dosage form. By doing this the
interaction between these two actives was avoided, thus reducing the impurity
formation & providing stable product with no or less side effects.
Obviousness:
Defendant argued that asserted claims are invalid as obvious
over certain prior arts. These prior arts disclosed claimed limitations such as
combination of actives, their dose, their interaction & formation of
impurity etc. One of them was US
2007/0043096, where dispute arose to determine whether it is a prior art under
102(a). [US’096 discloses unit dosage
form comprising ibuprofen & famotidine, in amounts suitable for three times
per day administration.] The
priority date of the US’033 patent is Nov. 2007. US’096 application was
published in Feb. 2007. Defendant argued that US’096 is “by another” as it
mentioned different inventors than the US’033. Plaintiff argued that it is not “by
another” because the inventive idea was conceived by same inventors mentioned
on both US’033 patent & US’096 application. Court, however disagreed &
said that claimed limitation regarding stability was not conceived by these
same inventors. It was a work from other inventor & therefore it is a prior
art under 102(a). Other prior arts disclosed other claimed limitations such as
impurity level, rapid dissolution, reduction of risk of ulcer etc. Plaintiff argued that there was not motivation
& reasonable expectation of success in combining these prior arts. But, district
court disagreed & said that POSA would have reasonable expectation of success
in doing so because most of things were
known in the art with rational behind that.
Indefiniteness:
Defendant argued that the “no more than about 1% sulfamide”
limitation is indefinite because scope of the invention in not clear to POSA.
Defendant argued that the ’033 patent does not define “sulfamide,” provides no
chemical name, structure or specific method of testing for “sulfamide,” does
not refer to the USP or Famotidine Impurity C, and does not provide any method
for identifying or quantifying “sulfamide” in a composition. Court, however,
disagreed & said that a POSA would understand “sulfamide” in the “no more
than about 1% sulfamide” limitation in all the asserted claims to be USP
Famotidine Impurity C. US’033 patent
explains that “sulfamide” is “a principal degradant of famotidine formed by the
interaction of famotidine and ibuprofen.” Therefore, “a POSA would have
understood that ‘sulfamide’ in the ’033 patent does not refer to the small
molecule sulfamide, but instead means Famotidine Impurity C in the USP because
it is the only known principal degradant that contains a sulfamide functional
group and that is formed as a result of the acid-catalyzed hydrolysis of
famotidine.”
Infringement:
Plaintiff argued that Alkem’s ANDA Product infringes the
asserted claims under DOE. Court’s construed - “a first portion” as reciting
“an ibuprofen compartment that is not a core” and “a second portion” as
reciting “a famotidine compartment that is not a shell”. Plaintiff applied DOE theory
to more than one claim element — “a first portion” and “a second portion” — at
the same time. Court said that Plaintiff was specifically instructed at trial
to provide legal support for this, which seemingly contradicts applying DOE on
an element-by-element basis, not to the invention as a whole. Court found DOE theory
inapplicable here but still proceeded with the analysis.
Alkem’s ANDA Product is a tablet-in-tablet dosage form with
a barrier-coated ibuprofen (800 mg) core portion and a famotidine (26.6 mg)
shell portion; on the other hand, the claimed composition required a famotidine
(26.6 mg) core and an ibuprofen (800 mg) shell, with an optional barrier layer.
Defendant argued the difference in design is not trivial stating that Alkem’s
ANDA Product is substantially different in at least two important ways –
stability and dissolution. In terms of stability, Alkem contended that the
asserted claims rely on the geometry of the small famotidine core to reduce
and/or minimize “the surface area of the core, or of direct physical contact
between the incompatible active pharmaceutical ingredients.” Moreover, a
barrier layer is optional in claimed invention due to the design of the
invention. This is not the case with defendant’s product. Court said that the inventive aspect of the
’033 patent is a stable pharmaceutical composition of famotidine and ibuprofen
in a single unit dosage form comprising a famotidine core, having a reduced or
minimal surface area, surrounded by a layer of ibuprofen. The specification
repeatedly highlights the increased stability provided by the disclosed
geometry. Unlike the pharmaceutical composition of the asserted claims,
Defendant’s ANDA Product must use a barrier layer and cannot rely on the
geometry of a small famotidine core. Therefore, in regard to stability,
Defendant’s ANDA Product is substantially different as geometry contributes
nothing to stability.
In terms of dissolution, Defendant argued that its ANDA
Product is substantially different from the claims. Defendant argued that when
DUEXIS® (commercial embodiment of the ’033 patent) is exposed to the
dissolution medium, the ibuprofen begins to dissolve from the shell immediately
and the famotidine does not begin to significantly dissolve until the
dissolution medium further penetrates into the core (i.e., about five minutes
later). When Alkem’s ANDA Product is exposed to the dissolution medium, the
famotidine begins to dissolve from the shell immediately and the ibuprofen does
not begin to significantly dissolve until the dissolution medium further
penetrates into the core (i.e., about fifteen minutes later). Court said that,
Defendant’s arguments are not as strong. While there is a discernable difference
in the release of the ibuprofen and famotidine in Defendant’s ANDA Product
occurring about fifteen minutes later than in DUEXIS®, the later release still
meets the claim limitation of “release of both the ibuprofen and the famotidine
occurring rapidly at about the same time” when “at about the same time” is
defined as the ‘033 patent specification defines it: “release of one API begins
before release of the second API is completed.”
Under “Function-Way-Result” test, Court agreed with
Defendant & said that the ’033 patent specification teaches the use of
geometry, with the option of a barrier layer. Moreover, using the design of the
present invention, the barrier layer can be omitted without sacrificing
stability. Under this view of the “function-way-result” test, while the
function and the result may be substantially the same, the way is not. The way
does not use geometry at all. As Alkem’s ANDA Product requires a barrier layer
as a consequence of its geometrical design, it does not infringe under the
“function-way-result” test.
