Humira® (Adalimumab) is a fully human monoclonal
antibody that binds to tumor necrosis factor-alpha (TNFα). Humira® reduces inflammatory response of
autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn's
disease, and ulcerative colitis. Humira®
has about $14.0 billion of sales globally.
Humira rights are owned by AbbVie.
AbbVie recently filed a suit against Amgen alleging
infringement of ten patents.[3] In the complaint AbbVie identified 61 patents (“Paragraph 3 List”) that it alleges
cover Amgen’s biosimilar product, but limited the infringement suit to only 10
patents (“Paragraph 5 List”) since Amgen allegedly agreed that the number of
patents that it would be sued on to be 6, for a maximum of 12 (6 patents from
each side). AbbVie asserts it can later seek
a preliminary injunction on the patents in the Paragraph 3 List that are not on
the Paragraph 5 List once Amgen serves a notice of commercial marketing.
The following table summarizes the
“biosimilar patent dance” between the parties as alleged by AbbVie in its
complaint:
Date
|
Section
|
Event
|
April
11, 2016
|
42
U.S.C § 262(l)(3)(A)
“Paragraph 3 List”
|
AbbVie
provided Amgen with a List of patents for which it believed a claim of patent
infringement could be reasonably asserted against Amgen’s adalimumab
biosimilar. (61 patents and 5 allowed patent applications).
|
April
25, 2016
|
42
U.S.C § 262(l)(7)
|
AbbVie
provided a supplemental patent List adding a recently issued patent (which
had been one of the 5 allowed patent applications on AbbVie’s 3A List)
|
May
10, 2016
|
42
U.S.C § 262(l)(7)
|
AbbVie
provided a second supplemental patent List adding two recently issued patents
(both of which had been Listed as patent applications on AbbVie’s 3A List).
|
June
9, 2016,
|
42
U.S.C § 262(l)(7)
|
AbbVie
provided a third supplemental patent List, identifying two more recently
issued patents (the last two patent applications from AbbVie’s 3A List).
|
June
10, 2016
|
42
U.S.C. § 262(l)(3)(B).
|
Amgen
responded by providing AbbVie with a statement contesting Amgen’s
infringement of certain patents and the validity of those patents.
|
June
21, 2016
|
42
U.S.C. § 262(l)(3)(C)
(“AbbVie’s
3C Statement”):
|
AbbVie
responded by providing Amgen with a nearly 1,500 page statement showing that
Amgen’s biosimilar product would infringe more than 1,100 claims of 60 AbbVie
patents and that those patent claims were valid. AbbVie also identified 6 patents that it
was no longer pursing an infringement claim on.
|
June 22, 2016
|
42
U.S.C § 262(l)(7)
|
AbbVie
provided a supplemental patent List adding recently issued patent U.S. Patent
No. 9,365,645. This brought the total number of patents asserted by AbbVie
against Amgen to 61.
|
Amgen
provided AbbVie with the number of patents that it would agree to be sued on.
That number was six. This meant that the maximum number of patents that could
be part of this first lawsuit under the BPCIA was twelve (six patents from
each side).
|
||
August
4, 2016
|
42
U.S.C. § 262(l)(5)
“Paragraph
5 List”
|
AbbVie
identified United States Patent Nos. 8,911,964; 8,916,157; 8,986,693;
8,961,973; 9,096,666; and 9,272,041. Amgen identified United States Patent Nos.
8,663,945; 8,986,693; 9,096,666; 9,220,781; 9,359,434; and 9,365,645. Given
there was overlap of 2 patents, there are 10 patents in the suit.
|
The following table has the patents on AbbVie’s and
Amgen’s Paragraph 5 Lists, as well as AbbVie’s patents that were subject of an
IPR (inter Partes Review) petition:
No.
|
Patents
Identified by AbbVie
|
Patents
Identified by Amgen
|
AbbVie’
patents in IPRs
|
Claim Summary
|
1
|
8,663,945
|
A
method of producing anti-TNF alpha antibody in a CHO cell; claims limited to
a specific antibody sequence.
|
||
2
|
8889135
IPR2016-00408
IPR2016-00409
IPR2016-00172
|
A
method for treating rheumatoid arthritis by
subcutaneous administration of an antibody; claims limited to a
specific antibody sequence.
|
||
3
|
8,916,157
|
8916157
IPR2015-01514
IPR
by Amgen
|
A
stable liquid aqueous pharmaceutical formulation of a human IgG1 anti-human
Tumor Necrosis Factor alpha antibody; claims limited to a specific antibody
sequence.
|
|
4
|
8916158
IPR2015-01517
IPR
by Amgen
|
A
stable liquid aqueous pharmaceutical formulation of a human IgG1 anti-human
Tumor Necrosis Factor alpha antibody; claims limited to a specific antibody
sequence.
|
||
5
|
8,911,964
|
A
fed-batch production method of making a human anti-TNF alpha by culturing CHO
cells.
|
||
6
|
8,961,973
|
A
multiple-variable dose method for inducing clinical remission of Crohn's
disease by administering an anti-TNF alpha antibody; claims limited to a
specific antibody sequence.
|
||
7
|
8,986,693
|
8,986,693
|
A
method for treating moderate to severe chronic plaque psoriasis by
administering adalimumab.
|
|
8
|
9017680
IPR2016-00188
|
A
method of reducing signs and symptoms in a patient with moderately to
severely active rheumatoid arthritis by
administering an anti-TNF alpha antibody; claims limited to a specific
antibody sequence.
|
||
9
|
9073987
IPR2016-00189
|
A
method of reducing signs and symptoms in a patient with moderately to
severely active rheumatoid arthritis by
administering an anti-TNF alpha antibody; claims limited to a specific
antibody sequence.
|
||
10
|
9,096,666
|
9,096,666
|
A
liquid composition comprising adalimumab
|
|
11
|
9114166
IPR2016-01018
|
A
stable liquid aqueous pharmaceutical formulation comprising: a human
anti-human Tumor Necrosis Factor alpha; claims limited to a specific antibody
sequence.
|
||
12
|
9,220,781
|
A
stable liquid aqueous pharmaceutical formulation comprising (a) a human IgG1
anti-human Tumor Necrosis Factor alpha; claims limited to a specific antibody
sequence.
|
||
13
|
9,272,041
|
A
stable liquid aqueous pharmaceutical formulation comprising (a) a human IgG1
anti-human Tumor Necrosis Factor alpha; claims limited to a specific antibody
sequence.
|
||
14
|
9,359,434
|
A
method for producing a composition comprising adalimumab, the method comprising
culturing a mammalian cell producing adalimumab in cell culture media.
|
||
15
|
9,365,645
|
A
composition comprising adalimumab with particular amounts of oligosaccharides.
|
These 15 patents from AbbVie’s Humira®
patent portfolio have so far garnered the most attention. They mostly cover various methods of
treatments and stable liquid formulations.
All of these 15 patents have claims that are limited by a sequence,
presumably that of adalimumab (Humira®). Interestingly, the Paragraph 5 Lists of AbbVie
and Amgen do not include a number of AbbVie patents that have been the subject
of IPR petitions. AbbVie, but not Amgen,
also included a patent (US Patent 8,916,157) for which Amgen petitioned the
PTAB to institute an IPR, which was denied.[5] Some of the patents in the Paragraph 5 Lists
have very similar claims to other patents on the Paragraph 3 List that may have
been left out due to the desire to not litigate over similar patents.
The following table includes AbbVie’s patents in AbbVie’s
Paragraph 5 List and Paragraph 3 List other than the 6 patents that AbbVie
alleges it withdrew. This table does not
include the additional 39 patents that AbbVie alleges cover Humira®
that AbbVie did not include in its Paragraph 3 List that it sent to Amgen.[6]
U.S. Patent No.
|
Title
|
Claim 1
|
Patents On
Both Paragraph 5 Lists
|
||
8,986,693
|
Use
of TNFα Inhibitor for Treatment of Psoriasis
|
1.
A method for treating moderate to severe chronic plaque psoriasis, comprising
subcutaneously administering to an adult patient having moderate to severe
chronic plaque psoriasis a first dose of 80 mg of adalimumab, followed by 40
mg of adalimumab every other week starting one week after said first dosing,
wherein the patient achieves at least Psoriasis Area and Severity Index
(PASI) 90 response at week 12 of the treatment.
|
9,096,666
|
Purified
Antibody Composition
|
1.
A liquid composition comprising adalimumab, wherein the adalimumab is
expressed in a Chinese Hamster Ovary (CHO) cell expression system; and the
composition is characterized in that when the composition is assayed in a
cathepsin L kinetic assay, a level of cathepsin L activity less than 1.84
RFU/s/mg of adalimumab is observed, wherein the cathepsin L kinetic assay
comprises: i) diluting the composition in a polystyrene container in a
solution containing 25 mM NaOAc, 5 mM DTT and 1 mM EDTA at pH 5.5, ii) adding
dextran sulfate to a concentration of 0.035 .mu.g/mL and incubating at
37.degree. C. for six hours, iii) adding Z-leucine-arginine covalently bound
at its C-terminus to a fluorescent 7-amino-4-methyl coumarin
(Z-leucine-arginine-AMC), wherein the diluting, adding, and incubating steps
are sufficient to permit the measurement of cathepsin L hydrolysis of the
Z-leucine-arginine-AMC within a linear range, and iv) measuring
Z-leucine-arginine-AMC hydrolysis in the linear range in RFU/s/mg of
adalimumab.
|
Patents On AbbVie’s
Paragraph 5 List Only
|
||
8,916,157
|
Formulation
of Human Antibodies for Treating TNF-Alpha Associated Disorders
|
1.
A stable liquid aqueous pharmaceutical formulation comprising (a) a human
IgG1 anti-human Tumor Necrosis Factor alpha (TNFα ) antibody, or an
antigen-binding portion thereof, at a concentration of 20 to 150 mg/ml, (b) a
tonicity agent, (c) a surfactant, and (d) a buffer system having a pH of 4.0
to 8.0, wherein the antibody comprises the light chain variable region and
the heavy chain variable region of D2E7.
|
8,911,964
|
Fed-Batch
Method of Making Human Anti-TNF-Alpha Antibody
|
1.
A fed-batch production method of making a human anti-TNFα antibody which comprises (1) a light chain
variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:1 and
(2) a heavy chain variable region comprising the amino acid sequence of SEQ
ID NO:2, said method comprising culturing Chinese Hamster Ovary (CHO) cells
comprising a nucleic acid encoding said anti-TNFα antibody in a cell culture production
medium in large-scale, wherein the glucose concentration in said medium is
monitored, the glucose concentration in said medium decreases to below 2 g/L,
and glucose is added to said medium when the glucose concentration in said
medium decreases to below 2 g/L, or the glucose concentration in said medium
is monitored and glucose is added to said medium to maintain the glucose
concentration in said medium at a concentration of at least 2 g/L but no
greater than 7 g/L, such that said anti-TNFα
antibody is produced at a titer of at least 2 g/L in said cell culture
production medium.
|
8,961,973
|
Multiple
Variable Dose Regimen for Treating TNFα
|
1.
A multiple-variable dose method for inducing clinical remission of Crohn's
disease in a subject in need thereof, comprising subcutaneously administering
to the subject: a first dose of 160 mg of a recombinant human anti-TNFα antibody administered to the subject within
a day; and a second dose of 80 mg of the antibody administered to the subject
within a day, wherein the second dose is administered two weeks following
administration of the first dose; wherein the antibody comprises: a heavy
chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:8; a
CDR2 comprising the amino acid sequence of SEQ ID NO:6; and a CDR3 comprising
the amino acid sequence of SEQ ID NO:4; and a light chain comprising a CDR1
comprising the amino acid sequence of SEQ ID NO:7; a CDR2 comprising the
amino acid sequence of SEQ ID NO:5; and a CDR3 comprising the amino acid sequence
of SEQ ID NO:3.
|
9,272,041
|
Formulation
of Human Antibodies for Treating TNF-α Associated Disorders
|
1.
A stable liquid aqueous pharmaceutical formulation comprising (a) a human
IgG1 anti-human Tumor Necrosis Factor alpha (TNFα ) antibody at a concentration
of 50 mg/ml, (b) a polyol, (c) a polysorbate, and (d) a buffer system
comprising acetate and having a pH of 4 to 8, wherein the antibody is D2E7,
and wherein the formulation is suitable for subcutaneous injection.
|
Patents On Amgen’s Paragraph 5 List
Only
|
||
8,663,945
|
Methods
of Producing Anti-TNF-Alpha Antibodies in Mammalian Cell Culture
|
1.
A method of producing an anti-TNFα antibody in a mammalian cell culture, said
method comprising: a) culturing Chinese Hamster Ovary (CHO) cells comprising
a nucleic acid encoding the antibody, or a fragment thereof, in a cell
culture growth medium to form the mammalian cell culture; and b) culturing
the CHO cells in a cell culture production medium, wherein glucose is added
to the mammalian cell culture to maintain a glucose concentration of at least
2 g/L, such that the anti-TNFα
antibody is produced, wherein the anti-TNFα antibody comprises a light chain variable
region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ
ID NO:3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:5, and
a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7, and
comprises a heavy chain variable region (HCVR) having a CDR3 domain
comprising the amino acid sequence of SEQ ID NO:4, a CDR2 domain comprising
the amino acid sequence of SEQ ID NO: 6, and a CDR1 domain comprising the
amino acid sequence of SEQ ID NO:8.
|
9,220,781
|
Formulation
of Human Antibodies for Treating TNF-α Associated Disorders
|
1.
A stable liquid aqueous pharmaceutical formulation comprising (a) a human
IgG1 anti-human Tumor Necrosis Factor alpha (TNFα ) antibody at a
concentration of 50 mg/ml, (b) a polyol, (c) a polysorbate, and (d) a buffer
system comprising an organic acid and having a pH of 4 to 8, wherein the
antibody is D2E7, and wherein the formulation is suitable for subcutaneous
injection.
|
9,365,645
|
Methods
for controlling the galactosylation profile of recombinantly-expressed
proteins
|
1.
A composition comprising an antibody comprising the heavy and light chain
variable domains of adalimumab, wherein less than 70% of the total N-linked
oligosaccharides present on said antibody are of an agalactosyl fucosylated
biantennary oligosaccharide form (sum NGA2F+NGA2F-GlcNAc).
|
9,359,434
|
Cell
Culture Methods to Reduce Acidic Species
|
1.
A method for producing a composition comprising adalimumab, the method
comprising culturing a mammalian cell producing adalimumab in cell culture
media comprising 2 g/L to 11 g/L of each of one or more basic amino acids, to
produce a composition comprising adalimumab, wherein the composition
comprises less than 20% total acidic species of adalimumab, wherein the
acidic species of adalimumab correspond to the peaks that elute earlier than
the main peak in a WCX-10 HPLC chromatogram of adalimumab, and wherein the
WCX-10 HPLC chromatogram is generated using a first mobile phase of 10 mM
Sodium Phosphate dibasic (pH 7.5) and a second mobile phase of 10 mM Sodium
Phosphate dibasic, 500 mM Sodium Chloride (pH 5.5), and wherein the WCX-10
HPLC chromatogram is generated using detection at 280 nm.
|
Patents On AbbVie’s
Paragraph 3 List (other than the 6 patents later withdrawn and 10 patents
above)
|
||
6,090,382
|
Human
antibodies that bind human TNFα
|
1. An isolated human antibody, or an
antigen-binding portion thereof, that dissociates from human TNFα with a Kd of 1 x 10-8
M or less and a Koff rate constant of 1 x 10-3 s-1
or less, both determined by surface plasmon resonance, and neutralizes human
TNFα cytotoxicity in a standard in
vitro L929 assay with an IC50 of 1 x 10-7 M or less.
|
8,889,135
|
Methods
of Administering Anti TNFα Antibodies
|
1.
A method for treating rheumatoid arthritis in a human subject, comprising
administering subcutaneously to a human subject having rheumatoid arthritis a
total body dose of 40 mg of a human anti-TNFα antibody once every 13 -15 days for a time
period sufficient to treat the rheumatoid arthritis, wherein the anti-TNFα antibody comprises an IgG1 heavy chain
constant region; a variable light ("VL") chain region
comprising a CDR1 having the amino acid sequence of SEQ ID NO:7, a CDR2
having the amino acid sequence of SEQ ID NO:5, and a CDR3 having the amino
acid sequence of SEQ ID NO:3; and a variable heavy ("VH")
chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:8,
a CDR2 having the amino acid sequence of SEQ ID NO:6 and a CDR3 having the
amino acid sequence of SEQ ID NO:4.
|
9,017,680
|
Methods
of Administering Anti TNFα Antibodies
|
1.
A method of reducing signs and symptoms in a patient with moderately to
severely active rheumatoid arthritis, comprising: administering to said
patient, in combination with methotrexate, a human anti-TNFα antibody, wherein the human anti-TNFα antibody is administered subcutaneously in a
total body dose of 40 mg once every 13-15 days, and wherein the anti-TNFα antibody comprises an IgG1 heavy chain
constant region; a variable light ("VL") chain region
comprising a CDR1 having the amino acid sequence of SEQ ID NO:7, a CDR2
having the amino acid sequence of SEQ ID NO:5, and a CDR3 having the amino
acid sequence of SEQ ID NO:3; and a variable heavy ("VH")
chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:8,
a CDR2 having the amino acid sequence of SEQ ID NO:6 and a CDR3 having the
amino acid sequence of SEQ ID NO:4.
|
9,073,987
|
Methods
of Administering Anti TNFα Antibodies
|
1.
A method of reducing signs and symptoms in a patient with moderately to severely
active rheumatoid arthritis, comprising: administering to said patient a
total body dose of 40 mg of a human anti-TNFα antibody, wherein the dose is administered
subcutaneously from a 40 mg dosage unit form once every 13-15 days, and
wherein the anti-TNFα antibody
comprises an IgG1 heavy chain constant region; a variable light ("VL")
chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:7,
a CDR2 having the amino acid sequence of SEQ ID NO:5, and a CDR3 having the
amino acid sequence of SEQ ID NO:3; and a variable heavy ("VH")
chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:8,
a CDR2 having the amino acid sequence of SEQ ID NO:6 and a CDR3 having the
amino acid sequence of SEQ ID NO:4.
|
8,911,737
|
Methods
of Administering Anti TNFα Antibodies
|
1.
A method for treating Crohn's disease in a human subject, comprising
administering subcutaneously to a human subject having Crohn's disease a
total body dose of 40 mg of a human anti-TNFα antibody once every 13-15 days for a time
period sufficient to treat Crohn's disease, wherein the anti-TNFα antibody comprises an IgG1 heavy chain
constant region; a variable light ("VL") chain region
comprising a CDR1 having the amino acid sequence of SEQ ID NO:7, a CDR2
having the amino acid sequence of SEQ ID NO:5, and a CDR3 having the amino
acid sequence of SEQ ID NO:3; and a variable heavy ("VH")
chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:
8, a CDR2 having the amino acid sequence of SEQ ID NO:6 and a CDR3 having the
amino acid sequence of SEQ ID NO:4.
|
8,974,790
|
Methods
of Administering Anti TNFα Antibodies
|
1.
A method for treating ulcerative colitis in a human subject, comprising
administering subcutaneously to a human subject having ulcerative colitis a
total body dose of 40 mg of a human anti-TNFα antibody once every 13-15 days for a time
period sufficient to treat the ulcerative colitis, wherein the anti-TNFα antibody comprises an IgG1 heavy chain
constant region; a variable light ("VL") chain region
comprising a CDR1 having the amino acid sequence of SEQ ID NO:7, a CDR2
having the amino acid sequence of SEQ ID NO:5, and a CDR3 having the amino
acid sequence of SEQ ID NO:3; and a variable heavy ("VH")
chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:8,
a CDR2 having the amino acid sequence of SEQ ID NO:6and a CDR3 having the
amino acid sequence of SEQ ID NO:4.
|
8,992,926
|
Methods
of Administering Anti TNFα Antibodies
|
1.
A method for treating rheumatoid spondylitis in a human subject, comprising
administering subcutaneously to a human subject having rheumatoid spondylitis
a total body dose of 40 mg of a human anti-TNFα antibody once every 13-15 days for a time
period sufficient to treat the rheumatoid spondylitis, wherein the anti-TNFα antibody comprises an IgG1 heavy chain
constant region; a variable light ("VL") chain region
comprising a CDR1 having the amino acid sequence of SEQ ID NO:7, a CDR2
having the amino acid sequence of SEQ ID NO:5, and a CDR3 having the amino
acid sequence of SEQ ID NO:3; and a variable heavy ("VH")
chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:8,
a CDR2 having the amino acid sequence of SEQ ID NO:6 and a CDR3 having the
amino acid sequence of SEQ ID NO:4.
|
8,889,136
|
Multiple
Variable Dose Regimen for Treating TNFα
|
1.
A multiple-variable dose method for inducing clinical remission of Crohn's
disease in a subject in need thereof, comprising subcutaneously administering
to the subject: a first dose of 160 mg of a recombinant human anti-TNFα antibody administered as a set of four
injections of 40 mg of the antibody administered to the subject within a day;
and a second dose of 80 mg of the antibody administered as a set of two injections
of 40 mg of the antibody administered to the subject within a day, wherein
the second dose is administered two weeks following administration of the
first dose; wherein the antibody comprises: a heavy chain comprising a CDR1
comprising the amino acid sequence of SEQ ID NO:8; a CDR2 comprising the
amino acid sequence of SEQ ID NO:6; and a CDR3 comprising the amino acid
sequence of SEQ ID NO:4; and a light chain comprising a CDR1 comprising the
amino acid sequence of SEQ ID NO:7; a CDR2 comprising the amino acid sequence
of SEQ ID NO:5; and a CDR3 comprising the amino acid sequence of SEQ ID NO:3.
|
8,961,974
|
Multiple
Variable Dose Regimen for Treating TNFα
|
1.
A multiple-variable dose method for treating ulcerative colitis in a subject
in need thereof, comprising subcutaneously administering to the subject: a
first dose of 160 mg of a recombinant human anti-TNFα antibody administered to the subject within
a day; and a second dose of 80 mg of the antibody administered to the subject
within a day, wherein the second dose is administered two weeks following
administration of the first dose; wherein the antibody comprises: a heavy
chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:8; a
CDR2 comprising the amino acid sequence of SEQ ID NO:6; and a CDR3 comprising
the amino acid sequence of SEQ ID NO:4; and a light chain comprising a CDR1
comprising the amino acid sequence of SEQ ID NO:7; a CDR2 comprising the
amino acid sequence of SEQ ID NO:5; and a CDR3 comprising the amino acid
sequence of SEQ ID NO:3.
|
9,061,005
|
Multiple
Variable Dose Regimen for Treating Idiopathic Inflammatory Bowel Disease
|
1.
A multiple-variable dose method for treating idiopathic inflammatory bowel
disease in a subject in need thereof, comprising subcutaneously administering
to the subject: a first dose of 160 mg of a recombinant human anti-TNFα antibody administered to the subject within
a day; and a second dose of 80 mg of the antibody administered to the subject
within a day, wherein the second dose is administered two weeks following
administration of the first dose; wherein the antibody comprises: a heavy
chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:8; a
CDR2 comprising the amino acid sequence of SEQ ID NO:6; and a CDR3 comprising
the amino acid sequence of SEQ ID NO:4; and a light chain comprising a CDR1
comprising the amino acid sequence of SEQ ID NO:7; a CDR2 comprising the
amino acid sequence of SEQ ID NO:5; and a CDR3 comprising the amino acid
sequence of SEQ ID NO:3.
|
9,187,559
|
Multiple
Variable Dose Regimen for Treating Idiopathic Inflammatory Bowel Disease
|
1.
A multiple-variable dose method for treating idiopathic inflammatory bowel
disease in a human subject in need thereof, comprising subcutaneously
administering to the human subject: a first dose of 160 mg of adalimumab
administered to the human subject within a day; and a second dose of 80 mg of
adalimumab administered to the human subject within a day, wherein the second
dose is administered two weeks following administration of the first dose.
|
9,090,689
|
Use
of TNFα Inhibitor for Treatment of Psoriasis
|
1.
A method of administering adalimumab for treatment of moderate to severe
chronic plaque psoriasis, comprising filling adalimumab into vessels and
subcutaneously administering 40 mg of said adalimumab to a patient having
moderate to severe chronic plaque psoriasis every other week.
|
8,906,373
|
Use
of TNFα Inhibitor for Treatment of Psoriasis
|
1.
A method of treatment of psoriasis in a patient with moderate to severe active
psoriatic arthritis (PsA), comprising subcutaneously administering to said
patient 40 mg adalimumab every other week, wherein said patient has .gtoreq.3
swollen and .gtoreq.3 tender joints prior to the treatment and has failed
NSAID therapy, and wherein said patient achieves a 90% reduction of the
Psoriasis Area and Severity Index Score (PASI 90) at week 24 of the
treatment.
|
9,085,620
|
Use
of TNFα Inhibitor for Treatment of Psoriatic Arthritis
|
1.
A method of administering adalimumab for treatment of psoriatic arthritis,
comprising filling adalimumab into vessels and subcutaneously administering
40 mg of said adalimumab to a patient having psoriatic arthritis every other
week.
|
9,067,992
|
Use
of TNFα Inhibitor for Treatment of Psoriatic Arthritis
|
1.
A method of treatment of moderate to severe active psoriatic arthritis in
adult patients, wherein each said patient has .gtoreq.3 swollen and .gtoreq.3
tender joints prior to the treatment and has failed NSAID therapy, comprising
subcutaneously administering to each said patient 40 mg of adalimumab every
other week, wherein 23% of said patients achieve 70% reduction in American
College of Rheumatology (ACR) score at week 24 of the treatment.
|
8,715,664
|
Use
of Human TNFα Antibodies for Treatment of Erosive Polyarthritis
|
1.
A method for inhibiting radiographic disease progression in a human subject
having erosive polyarthritis associated with a disorder in which TNFα activity is detrimental, comprising
administering to the subject having erosive polyarthritis an isolated human
anti-TNFα antibody, or antigen-binding
portion thereof, such that radiographic disease progression is inhibited in
the subject, wherein a Total Sharp Score (TSS) of the subject is either
maintained or decreased following administration of the human anti-TNFα antibody, or antigen-binding portion
thereof, wherein the human anti-TNFα antibody, or an antigen-binding portion
thereof, dissociates from human TNFα with a Kd of 1.times.10.sup.-8 M
or less and a Koff rate constant of 1 x10-3 s-1
or less, both determined by surface plasmon resonance, and neutralizes human
TNFα cytotoxicity in a standard in
vitro L929 assay with an IC50 of 1x10-7 M or less.
|
8,808,700
|
Use
of TNF Alpha Inhibitor for Treatment of Erosive Polyarthritis
|
1.
A method for treating erosive polyarthritis, comprising administering a human
anti-TNFα antibody to a human subject
having erosive polyarthritis associated with psoriatic arthritis, ankylosing
spondylitis or juvenile rheumatoid arthritis, wherein a modified Total Sharp
Score (mTSS) of the subject is maintained or decreased following said
treating as compared to baseline prior to said treating, and wherein the
human anti-TNFα antibody comprises (1)
a light chain variable region (LCVR) comprising the amino acid sequence of
SEQ ID NO: 1 and (2) a heavy chain variable region (HCVR) comprising the
amino acid sequence of SEQ ID NO: 2.
|
8,999,337
|
Methods
for Treating Juvenile Idiopathic Arthritis by Inhibition of TNFα
|
1.
A method for treating juvenile idiopathic arthritis (JIA) in a subject
comprising administering an isolated human anti-TNFα antibody, or an
antigen-binding portion thereof, to the subject, wherein 20 mg of the
anti-TNFα antibody, or antigen-binding portion thereof, is administered to
the subject if the subject weighs less than 30 kg, or wherein 40 mg of the
anti-TNFα antibody, or antigen-binding portion thereof, is administered to
the subject if the subject weighs more than or equal to 30 kg.
|
9,284,370
|
Methods
for Treating Juvenile Idiopathic Arthritis
|
1.
A method for treating polyarticular juvenile idiopathic arthritis in a
subject comprising subcutaneously administering adalimumab to the subject
every other week, wherein 20 mg of adalimumab is administered to the subject
every other week if the subject weighs at least 15 kg and less than 30 kg, or
wherein 40 mg of adalimumab is administered to the subject every other week
if the subject weighs more than or equal to 30 kg.
|
8,802,100
|
Formulation
of Human Antibodies for Treating TNF-Alpha Associated Disorders
|
1.
A stable liquid aqueous pharmaceutical formulation comprising (a) a human
IgG1 anti-human Tumor Necrosis Factor alpha (TNFα ) antibody, or an
antigen-binding portion thereof, at a concentration of 45 to 150 mg/ml, (b) a
polyol, (c) a polysorbate at a concentration of 0.1 to 10 mg/ml, and (d) a
buffer system having a pH of 4.5 to 7.0, wherein the antibody comprises the
light chain variable region and the heavy chain variable region of D2E7.
|
8,802,101
|
Formulation
of Human Antibodies for Treating TNF-Alpha Associated Disorders
|
1.
A stable liquid aqueous pharmaceutical formulation comprising (a) a human
IgG1 anti-human Tumor Necrosis Factor alpha (TNFα ) antibody, or an
antigen-binding portion thereof, at a concentration of 45 to 105 mg/ml, (b) a
polyol, (c) a polysorbate at a concentration of 0.1 to 10 mg/ml, and (d) a
buffer system comprising acetate and having a pH of 4.5 to 7.0, wherein the
antibody comprises the light chain variable region and the heavy chain
variable region of D2E7.
|
8,916,158
|
Formulation
of Human Antibodies for Treating TNF-α Associated Disorders
|
1.
A stable liquid aqueous pharmaceutical formulation comprising (a) a human
IgG1 anti-human Tumor Necrosis Factor alpha (TNFα ) antibody, or an
antigen-binding portion thereof, at a concentration of 20 to 150 mg/ml, (b) a
polyol, (c) a surfactant, and (d) a buffer system having a pH of 4 to 8,
wherein the antibody comprises the light chain variable region and the heavy
chain variable region of D2E7.
|
9,114,166
|
Formulation
of Human Antibodies for Treating TNF-α Associated Disorders
|
1.
A stable liquid aqueous pharmaceutical formulation comprising: a human
anti-human Tumor Necrosis Factor alpha (TNFα ) IgG1 antibody at a
concentration of 50 mg/ml, wherein the antibody comprises the light chain
variable region and the heavy chain variable region of D2E7, and a buffer
system; wherein the formulation is isotonic, suitable for single-use
subcutaneous injection, and has a pH of 4.0 to 8.0.
|
9,302,011
|
Formulation
of Human Antibodies for Treating TNF-α Associated Disorders
|
1.
A stable liquid aqueous pharmaceutical formulation comprising (a) 50 mg/ml of
a human IgG1 anti-human Tumor Necrosis Factor alpha (TNFα ) antibody, wherein
the antibody comprises a light chain variable region comprising the amino
acid sequence of SEQ ID NO:1 and a heavy chain variable region comprising the
amino acid sequence of SEQ ID NO: 2; (b) a polyol; (c) a polysorbate; and (d)
a buffer system comprising an organic acid; wherein the formulation has a pH
of 4 to 8, and wherein the formulation is suitable for subcutaneous
injection.
|
9,102,723
|
Purified
Antibody Composition
|
1.
A method for preparing an adalimumab formulation, comprising the step of
mixing a liquid composition comprising adalimumab with a pharmaceutically
acceptable carrier, wherein the adalimumab is expressed in a Chinese Hamster
Ovary (CHO) cell expression system, and the composition is characterized in
that when the composition is assayed in a cathepsin L kinetic assay, a level
of cathepsin L activity of less than 1.84 RFU/s/mg of adalimumab is observed,
wherein the cathepsin L kinetic assay comprises: i) diluting the composition
in a polystyrene container in a solution containing 25 mM NaOAc, 5 mM DTT and
1 mM EDTA at pH 5.5, ii) adding dextran sulfate to a concentration of 0.035
.mu.g/mL and incubating at 37.degree. C. for six hours, iii) adding
Z-leucine-arginine covalently bound at its C-terminus to a fluorescent
7-amino-4-methyl coumarin (Z-leucine-arginine-AMC), wherein the diluting,
adding, and incubating steps are sufficient to permit the measurement of
cathepsin L hydrolysis of the Z-leucine-arginine-AMC within a linear range,
and iv) measuring Z-leucine-arginine-AMC hydrolysis in the linear range in
RFU/s/mg of adalimumab.
|
9,273,132
|
Purified
Antibody Composition
|
1.
A method of treating a disorder in which TNFα activity is detrimental in a subject, the
method comprising administering a liquid pharmaceutical composition
comprising a therapeutically effective amount of adalimumab and a
pharmaceutically acceptable carrier to the subject such that the disorder is
treated, wherein the adalimumab is produced in a Chinese Hamster Ovary (CHO)
cell expression system; wherein the disorder is selected from the group
consisting of rheumatoid arthritis, Crohn's disease, ulcerative colitis,
ankylosing spondylitis, psoriatic arthritis, psoriasis, hidradenitis
suppurativa, and juvenile rheumatoid arthritis; and wherein the composition
is characterized in that when the composition is assayed in a cathepsin L
kinetic assay, a level of cathepsin L activity less than 1.84 RFU/s/mg of
adalimumab is observed, wherein the cathepsin L kinetic assay comprises: i) diluting
the composition in a polystyrene container in a solution containing 25 mM
NaOAc, 5 mM DTT and 1 mM EDTA at pH 5.5, ii) adding dextran sulfate to a
concentration of 0.035 .mu.g/mL and incubating at 37.degree. C. for six
hours, iii) adding Z-leucine-arginine covalently bound at its C-terminus to a
fluorescent 7-amino-4-methyl coumarin (Z-leucine-arginine-AMC), wherein the
diluting, adding, and incubating steps are sufficient to permit the
measurement of cathepsin L hydrolysis of the Z-leucine-arginine-AMC within a
linear range, and iv) measuring Z-leucine-arginine-AMC hydrolysis in the
linear range in RFU/s/mg of adalimumab.
|
8,916,153
|
Purified
Antibody Composition
|
1.
A pharmaceutical composition comprising adalimumab and a pharmaceutically
acceptable carrier, wherein the adalimumab is produced in a Chinese Hamster
Ovary (CHO) cell expression system; and wherein the composition is
characterized in that when the composition is assayed in a cathepsin L
kinetic assay, a level of cathepsin L activity from 0.4 to less than 1.84
RFU/s/mg of adalimumab is observed, wherein the cathepsin L kinetic assay
comprises: i) diluting the composition in a polystyrene container in a
solution containing 25 mM NaOAc, 5 mM DTT and 1 mM EDTA at pH 5.5, ii) adding
dextran sulfate to a concentration of 0.035 .mu.g/mL and incubating at 37°C.
for six hours, iii) adding Z-leucine-arginine covalently bound at its
C-terminus to a fluorescent 7-amino-4-methyl coumarin
(Z-leucine-arginine-AMC), wherein the diluting, adding, and incubating steps
are sufficient to permit the measurement of cathepsin L hydrolysis of the
Z-leucine-arginine-AMC within a linear range, and iv) measuring
Z-leucine-arginine-AMC hydrolysis in the linear range in RFU/s/mg of
adalimumab.
|
8,895,009
|
Purified
Antibody Composition
|
1.
A liquid composition comprising adalimumab, wherein the adalimumab is
expressed in a Chinese Hamster Ovary (CHO) cell expression system; and
wherein the composition is characterized in that when the composition is
assayed in a cathepsin L kinetic assay, a level of cathepsin L activity from
0.4 to less than 1.84 RFU/s/mg of adalimumab is observed, wherein the
cathepsin L kinetic assay comprises: i) diluting the composition in a
polystyrene container in a solution containing 25 mM NaOAc, 5 mM DTT and 1 mM
EDTA at pH 5.5, ii) adding dextran sulfate to a concentration of 0.035
.mu.g/mL and incubating at 37.degree. C. for six hours, iii) adding
Z-leucine-arginine covalently bound at its C-terminus to a fluorescent
7-amino-4-methyl coumarin (Z-leucine-arginine-AMC), wherein the diluting,
adding, and incubating steps are sufficient to permit the measurement of
cathepsin L hydrolysis of the Z-leucine-arginine-AMC within a linear range,
and iv) measuring Z-leucine-arginine-AMC hydrolysis in the linear range in
RFU/s/mg of adalimumab.
|
8,883,156
|
Purified
Antibody Composition
|
1.
A method of treating a disorder in which TNFα activity is detrimental in a subject, the
method comprising administering a composition comprising a therapeutically
effective amount of adalimumab to the subject such that the disorder is
treated, wherein the adalimumab is produced in a Chinese Hamster Ovary (CHO)
cell expression system; wherein the disorder is selected from the group
consisting of rheumatoid arthritis, Crohn's disease, ulcerative colitis,
ankylosing spondylitis, psoriatic arthritis, psoriasis, and juvenile
rheumatoid arthritis; and wherein the composition is characterized in that
when the composition is assayed in a cathepsin L kinetic assay, a level of
cathepsin L activity from 0.4 to less than 1.84 RFU/s/mg of adalimumab is
observed, wherein the cathepsin L kinetic assay comprises: i) diluting the
composition in a polystyrene container in a solution containing 25 mM NaOAc,
5 mM DTT and 1 mM EDTA at pH 5.5, ii) adding dextran sulfate to a
concentration of 0.035 .mu.g/mL and incubating at 37.degree. C. for six
hours, iii) adding Z-leucine-arginine covalently bound at its C-terminus to a
fluorescent 7-amino-4-methyl coumarin (Z-leucine-arginine-AMC), wherein the
diluting, adding, and incubating steps are sufficient to permit the
measurement of cathepsin L hydrolysis of the Z-leucine-arginine-AMC within a
linear range, and iv) measuring Z-leucine-arginine-AMC hydrolysis in the
linear range in RFU/s/mg of adalimumab.
|
8,906,372
|
Purified
Antibody Composition
|
1.
A method of treating a disorder in which TNFα activity is detrimental in a subject, the
method comprising administering a composition comprising a therapeutically
effective amount of adalimumab to the subject such that the disorder is
treated, wherein the adalimumab is produced in a Chinese Hamster Ovary (CHO)
cell expression system; wherein the disorder is selected from the group
consisting of rheumatoid arthritis, Crohn's disease, ulcerative colitis,
ankylosing spondylitis, psoriatic arthritis, psoriasis, and juvenile
rheumatoid arthritis; and wherein the composition is characterized in that
when the composition is assayed in a cathepsin L kinetic assay, a level of
cathepsin L activity from 0.6 to less than 1.84 RFU/s/mg of adalimumab is
observed, wherein the cathepsin L kinetic assay comprises: i) diluting the
composition in a polystyrene container in a solution containing 25 mM NaOAc,
5 mM DTT and 1 mM EDTA at pH 5.5, ii) adding dextran sulfate to a
concentration of 0.035 .mu.g/mL and incubating at 37.degree. C. for six
hours, iii) adding Z-leucine-arginine covalently bound at its C-terminus to a
fluorescent 7-amino-4-methyl coumarin (Z-leucine-arginine-AMC), wherein the
diluting, adding, and incubating steps are sufficient to permit the
measurement of cathepsin L hydrolysis of the Z-leucine-arginine-AMC within a
linear range, and iv) measuring Z-leucine-arginine-AMC hydrolysis in the
linear range in RFU/s/mg of adalimumab.
|
9,328,165
|
Purified
Antibody Composition
|
1.
A liquid pharmaceutical composition comprising adalimumab and one or more of
sorbitol, a sugar, glycerol, or a preservative, wherein the adalimumab is
expressed in a Chinese Hamster Ovary (CHO) cell expression system; and the
composition is characterized in that when the composition is assayed in a
cathepsin L kinetic assay, a level of cathepsin L activity no greater than
1.3 RFU/s/mg of adalimumab is observed, wherein the cathepsin L kinetic assay
comprises: i.) diluting the composition in a polystyrene container in a
solution containing 25 mM NaOAc, 5 mM DTT and 1 mM EDTA at pH 5.5, ii.)
adding dextran sulfate to a concentration of 0.035 .mu.g/mL and incubating at
37.degree. C. for six hours, iii.) adding Z-leucine-arginine covalently bound
at its C-terminus to a fluorescent 7-amino-4-methyl coumarin
(Z-leucine-arginine-AMC), wherein the diluting, adding, and incubating steps
are sufficient to permit the measurement of cathepsin L hydrolysis of the
Z-leucine-arginine-AMC within a linear range, and iv.) measuring
Z-leucine-arginine-AMC hydrolysis in the linear range in RFU/s/mg of
adalimumab.
|
8,231,876
|
Purified
Antibody Composition
|
1.
A host cell protein (HCP)-reduced antibody preparation produced by a method
comprising: applying a mixture comprising an antibody and at least one HCP to
a cation exchange resin in an equilibration buffer, wherein greater than 30
grams of antibody per liter of cation exchange resin are applied; washing HCP
from the cation exchange resin with a plurality of wash steps comprising a
first wash and a second wash, wherein there is an increase in conductivity
from the first wash to the second wash; eluting the antibody from the cation
exchange resin with an elution buffer to form a first eluate; applying the
first eluate to an anion exchange resin, wherein prior to applying the first
eluate to the anion exchange resin, pH and conductivity of the first eluate
are adjusted to be substantially similar to pH and conductivity of the anion
exchange resin; and obtaining a first flowthrough comprising the antibody,
such that the HCP-reduced antibody preparation is obtained, wherein the
antibody is an isolated human anti-TNF.alpha. antibody that dissociates from
human TNF.alpha. with a Kd of 1 x 10-8 M or less and a
Koff rate constant of 1 x 10-3 s-1 or less,
both determined by surface plasmon resonance, and neutralizes human
TNF.alpha. cytotoxicity in a standard in vitro L929 assay with an IC50
of 1 x10-7 M or less, and wherein the HCP-reduced antibody
preparation comprises no greater than about 70 ng of HCP per mg of antibody
as measured by a HCP ELISA and a cathepsin L activity of no greater than
about 3.0 RFU/s/mg antibody.
|
8,906,646
|
Fed-Batch
Method of Making Human Anti-TNF-Alpha Antibody
|
1.
A fed-batch method of making a human anti-TNFα antibody comprising a light chain variable
region (LCVR) comprising the sequence of SEQ ID NO:1 and a heavy chain
variable region (HCVR) comprising the sequence of SEQ ID NO:2, said method
comprising culturing Chinese Hamster Ovary (CHO) cells comprising a nucleic
acid encoding said LCVR and HCVR of said anti-TNFα antibody in a cell culture production medium
in large-scale, wherein glucose concentration in said cell production medium
is monitored, the glucose concentration in said medium decreases to below 2
g/L, and glucose is added to said medium when the glucose concentration in
said medium decreases to below 2 g/L, or the glucose concentration in said
medium is monitored and glucose is added to said medium to maintain the
glucose concentration in said medium at a concentration of at least 2 g/L but
no greater than 7 g/L, such that said anti-TNFα antibody is produced, and wherein said
produced antibody is further affinity purified using a Protein A resin.
|
9,073,988
|
Fed
Batch Method of Making Antibodies
|
1.
A fed batch method for making an anti-TNFα antibody comprising a light chain variable
region (LCVR) comprising the sequence of SEQ ID NO:1 and a heavy chain
variable region (HCVR) comprising the sequence of SEQ ID NO:2, said method
comprising culturing mammalian cells comprising a nucleic acid encoding said
anti-TNFα antibody in a cell culture production medium in large scale,
wherein the pH of the cell culture production medium is adjusted according to
a pH linear ramp comprising beginning at a starting pH and ending at a final
pH that is less than the starting pH, such that said anti-TNFα antibody is
produced, and wherein said produced anti-TNFα antibody is further affinity
purified using a Protein A resin.
|
9,090,867
|
Fed
Batch Method of Making Antibody
|
1.
A fed-batch method for making an anti-TNFα antibody comprising a light chain
variable region (LCVR) comprising the sequence of SEQ ID NO:1 and a heavy
chain variable region (HCVR) comprising the sequence of SEQ ID NO:2, said
method comprising culturing mammalian cells comprising a nucleic acid encoding
said anti-TNFα antibody in a cell
culture production medium in large scale, wherein the pH of the cell culture
production medium is adjusted such that the culturing begins at a starting pH
and ends at a final pH that is less than the starting pH, such that said
anti-TNFα antibody is produced at a titer of at least 2 g/L in said cell
culture production medium.
|
9,234,032
|
Fed-Batch
Methods for Producing Adalimumab
|
1.
A fed-batch method for producing adalimumab in mammalian cells in culture,
wherein said mammalian cells express said adalimumab, the method comprising:
culturing the mammalian cells in a cell culture production medium in large
scale at a first temperature; and then reducing the temperature under which
the mammalian cells are cultured to a second lower temperature during
adalimumab production, wherein said adalimumab is produced at a titer of at
least 1.3 g/L in said cell culture and said adalimumab is further purified by
a process including Protein A affinity chromatography.
|
9,284,371
|
Methods
of Producing Adalimumab
|
1.
A method of producing adalimumab, comprising culturing in large-scale
mammalian cells that express adalimumab in a cell culture production medium,
wherein the pH of the cell culture production medium is adjusted from a first
pH to a second pH during said culturing, the second pH being lower than the
first pH, and the cell culture production medium is not removed but is
supplemented with glucose or one or more other nutrients at least once during
adalimumab production; and wherein adalimumab produced by the mammalian cells
is purified from the cell culture production medium using a process including
Protein A affinity purification.
|
9,206,390
|
Methods
to Control Protein Heterogeneity
|
1.
A method for controlling the oligosaccharide distribution of a
recombinantly-expressed immunoglobulin comprising supplementing during a
production stage a cell culture media used in the recombinant expression of
said immunoglobulin with a yeast hydrolysate supplement and/or a plant
hydrolysate supplement to achieve a yeast hydrolysate concentration in the
media of at least 11 g/L and/or a plant hydrolysate concentration of at least
7 g/L and assessing the oligosaccharide distribution of the
recombinantly-expressed immunoglobulin, thereby controlling the oligosaccharide
distribution of the recombinantly-expressed immunoglobulin, wherein the level
of agalactosyl fucosylated biantennary oligosaccharides (sum of NGA2F and
NGA2F-G1cNac) present on the recombinantly-expressed immunoglobulin is
decreased as compared to the level of agalactosyl fucosylated biantennary
oligosaccharides (sum of NGA2F and NGA2F-G1cNac) of the immunoglobulin
recombinantly-expressed in cell culture media which is not supplemented with
said yeast hydrolysate supplement and/or said plant hydrolysate supplement
during the production stage; and/or wherein the level of galactose containing
fucosylated biantennary oligossacharides (sum of NA1F and NA2F) present on
the recombinantly-expressed immunoglobulin is increased as compared to the
level of galactose containing fucosylated biantennary oligossacharides (sum
of NA1F and NA2F) of the immunoglobulin recombinantly-expressed in cell
culture media which is not supplemented with said yeast hydrolysate
supplement and/or said plant hydrolysate supplement during the production
stage.
|
9,290,568
|
Methods
to Control Protein Heterogeneity
|
1.
A process for producing a recombinantly-expressed immunoglobulin comprising a
heavy chain variable region comprising the sequence of SEQ ID NO: 2 and a
light chain variable region comprising the sequence of SEQ ID NO: 7,
comprising culturing a mammalian cell which recombinantly expresses the
immunoglobulin during a production stage in a cell culture media comprising
at least 0.4 g/L of asparagine, thereby producing the recombinantly-expressed
immunoglobulin, wherein the level of agalactosyl fucosylated biantennary
oligosaccharides (sum of NGA2F and NGA2F-GlcNac) present on the produced
immunoglobulin is increased as compared to the level of agalactosyl
fucosylated biantennary oligosaccharides (sum of NGA2F and NGA2F-GlcNac) of
immunoglobulin produced in cell culture media which does not comprise said
asparagine during the production stage; and/or wherein the level of galactose
containing fucosylated biantennary oligossacharides (sum of NA1F and NA2F)
present on the produced immunoglobulin is decreased as compared to the level
of galactose containing fucosylated biantennary oligossacharides (sum of NA1F
and NA2F) of immunoglobulin produced in cell culture media which does not comprise
said asparagine during the production stage.
|
9,234,033
|
Methods
to Control Protein Heterogeneity
|
1.
A process for producing a recombinantly-expressed immunoglobulin comprising a
heavy chain variable region comprising the sequence of SEQ ID NO: 2 and a
light chain variable region comprising the sequence of SEQ ID NO: 7,
comprising culturing a mammalian cell which recombinantly expresses the immunoglobulin
in a cell culture media comprising a yeast hydrolysate and/or a plant
hydrolysate, thereby producing the recombinantly-expressed immunoglobulin,
wherein the level of agalactosyl fucosylated biantennary oligosaccharides
(sum of NGA2F and NGA2F-GlcNac) present on the produced immunoglobulin is
decreased as compared to the level of agalactosyl fucosylated biantennary
oligosaccharides (sum of NGA2F and NGA2F-GlcNac) of immunoglobulin produced
in cell culture media which does not comprise said yeast hydrolysate, and/or
said plant hydrolysate; and/or wherein the level of galactose containing
fucosylated biantennary oligosaccharides (sum of NA1F and NA2F) present on
the produced immunoglobulin is increased as compared to the level of
galactose containing fucosylated biantennary oligosaccharides (sum of NA1F
and NA2F) of immunoglobulin produced in cell culture media which does not
comprise said yeast hydrolysate and/or said plant hydrolysate; and wherein
the level of agalactosyl fucosylated biantennary oligosaccharides (sum of
NGA2F and NGA2F-GlcNAc) present on the produced immunoglobulin is 66%-69%;
and/or wherein the level of fucosylated biantennary oligosaccharides (sum of
NA1F and NA2F) present on the produced immunoglobulin is 29%-31%.
|
9,085,618
|
Low
Acidic Species Compositions and Methods for Producing and Using the Same
|
1.
A low acidic species composition comprising adalimumab, wherein the
composition comprises less than 10% total acidic species of adalimumab and
wherein less than 75% of the lysine variant species of the composition have
zero C-terminal lysines (Lys 0), and wherein the acidic species of adalimumab
are quantified based on the relative area percent of peaks that elute earlier
than the main peak in a WCX-10 HPLC chromatogram of adalimumab wherein the
WCX-10 HPLC chromatogram is generated using a first mobile phase of 10mM
Sodium Phosphate dibasic (pH 7.5) and a second mobile phase of 10mM Sodium
Phosphate dibasic, 500 mM Sodium Chloride (pH 5.5) and wherein the WCX-10
HPLC chromatogram is generated using detection at 280 nm.
|
9,200,069
|
Low
Acidic Species Compositions and Methods for Producing and Using the Same
|
1.
A method of making a pharmaceutical composition, comprising mixing (a) 25-100
mg of a low acidic species composition comprising adalimumab, wherein the low
acidic species composition comprises less than 10% total acidic species of
adalimumab, wherein the acidic species of adalimumab have a net negative
charge relative to the adalimumab main species and the acidic species comprise
species selected from the group consisting of charge variants, structure
variants, fragmentation variants and any combinations thereof; wherein the
acidic species of adalimumab do not include process-related impurities
selected from the group consisting of host cell proteins, host cell nucleic
acids, chromatographic materials and media components, and wherein said low
acidic species adalimumab composition demonstrates increased cartilage
penetration as compared to a non-low acidic species composition of
adalimumab; and (b) a pharmaceutically acceptable carrier, thereby making a
pharmaceutical composition.
|
9,200,070
|
Low
Acidic Species Compositions and Methods for Producing and Using the Same
|
1.
A low acidic species adalimumab pharmaceutical composition suitable for
administration to a human subject comprising 40 mg of adalimumab wherein the
low acidic species adalimumab pharmaceutical composition comprises less than
10% total acidic species of adalimumab, wherein the acidic species of
adalimumab have a net negative charge relative to the adalimumab main species
and the acidic species comprise species selected from the group consisting of
charge variants, structure variants, fragmentation variants and any
combinations thereof; wherein the acidic species of adalimumab do not include
process-related impurities selected from the group consisting of host cell
proteins, host cell nucleic acids, chromatographic materials and media
components; and wherein said low acidic species adalimumab pharmaceutical
composition demonstrates increased cartilage penetration as compared to a
non-low acidic species composition of adalimumab; and a pharmaceutically
acceptable carrier.
|
9,334,319
|
Low
Acidic Species Compositions
|
1.
A composition comprising adalimumab, wherein the composition comprises less
than 10% total acidic species of adalimumab, wherein the acidic species of
adalimumab correspond to the peaks that elute earlier than the main peak in a
WCX-10 HPLC chromatogram of adalimumab, wherein the WCX-10 HPLC chromatogram
is generated using a first mobile phase of 10 mM Sodium Phosphate dibasic (pH
7.5) and a second mobile phase of 10 mM Sodium Phosphate dibasic, 500 mM
Sodium Chloride (pH 5.5), and wherein the WCX-10 HPLC chromatogram is
generated using detection at 280 nm.
|
9,315,574
|
Low
Acidic Species Compositions and Methods for Producing and Using the Same
|
1.
A method for producing a composition comprising an immunoglobulin comprising
the 6 CDR domains of adalimumab, the method comprising: contacting a first
sample comprising the immunoglobulin, wherein the sample comprises more than
10% total acidic species of the immunoglobulin, to a first chromatography
media in the presence of a loading buffer to produce a first chromatography
sample, wherein the first chromatography media is selected from the group
consisting of an ion exchange chromatography media, an affinity
chromatography media and a hydrophobic interaction chromatography (HIC)
media, wherein the first chromatography sample comprises a composition of the
immunoglobulin comprising less than 10% total acidic species of the
immunoglobulin, wherein the acidic species of the immunoglobulin correspond
to the peaks that elute earlier than the main peak in a WCX-10 HPLC
chromatogram of the immunoglobulin, wherein the WCX-10 HPLC chromatogram is
generated using a first mobile phase of 10 mM Sodium Phosphate dibasic (pH
7.5) and a second mobile phase of 10 mM Sodium Phosphate dibasic, 500 mM
Sodium Chloride (pH 5.5), and wherein the WCX-10 HPLC chromatogram is
generated using detection at 280 nm.
|
9,346,879
|
Protein
Purification Methods to Reduce Acidic Species
|
1.
A method for producing a composition comprising adalimumab, the method
comprising: contacting a first sample comprising adalimumab comprising more than
10% total acidic species of adalimumab to a first chromatography media in the
presence of a loading buffer, wherein the first chromatography media is
selected from the group consisting of an ion exchange chromatography media,
an affinity chromatography media and a hydrophobic interaction chromatography
(HIC) media, and collecting a first chromatography sample, wherein the first
chromatography sample comprises a composition of adalimumab comprising less
than 10% total acidic species of adalimumab, wherein the acidic species of
adalimumab correspond to the peaks that elute earlier than the main peak in a
WCX-10 HPLC chromatogram of adalimumab, wherein the WCX-10 HPLC chromatogram
is generated using a first mobile phase of 10 mM Sodium Phosphate dibasic (pH
7.5) and a second mobile phase of 10 mM Sodium Phosphate dibasic, 500 mM
Sodium Chloride (pH 5.5), and wherein the WCX-10 HPLC chromatogram is
generated using detection at 280 nm.
|
9,150,645
|
Cell
Culture Methods to Reduce Acidic Species
|
1.
A method for producing a composition comprising adalimumab, the method
comprising culturing a mammalian cell producing adalimumab in cell culture
media comprising 2 g/L to 11 g/L of each of one or more basic amino acids
selected from the group consisting of arginine, lysine, ornithine and
histidine, and combinations thereof, to produce a composition comprising
adalimumab, wherein the composition comprises less than 20% total acidic
species of adalimumab, wherein the acidic species of adalimumab do not
include process-related impurities selected from the group consisting of host
cells and lysed host cells and wherein the acidic species of adalimumab
correspond to the peaks that elute earlier than the main peak in a WCX-10
HPLC chromatogram of adalimumab, and wherein the WCX-10 HPLC chromatogram is
generated using a first mobile phase of 10 mM Sodium Phosphate dibasic (pH
7.5) and a second mobile phase of 10 mM Sodium Phosphate dibasic, 500 mM
Sodium Chloride (pH 5.5), and wherein the WCX-10 HPLC chromatogram is
generated using detection at 280 nm.
|
9,266,949
|
Low
Acidic Species Compositions and Methods for Producing and Using the Same
|
1.
A method for producing a composition comprising an immunoglobulin comprising
the 6 CDR domains of adalimumab, the method comprising: culturing a mammalian
cell producing an immunoglobulin comprising the 6 CDR domains of adalimumab
in a cell culture media comprising 2 g/L to 11 g/L of each of one or more
basic amino acids selected from the group consisting of arginine, lysine,
ornithine and histidine, and combinations thereof, to produce a composition
comprising an immunoglobulin comprising the 6 CDR domains of adalimumab,
wherein the composition comprises less than 20% total acidic species of the
immunoglobulin, and wherein the acidic species of the immunoglobulin
correspond to the peaks that elute earlier than the main peak in a WCX-10
HPLC chromatogram of the immunoglobulin, and wherein the WCX-10 HPLC
chromatogram is generated using a first mobile phase of 10 mM Sodium
Phosphate dibasic (pH 7.5) and a second mobile phase of 10 mM Sodium
Phosphate dibasic, 500 mM Sodium Chloride (pH 5.5), and wherein the WCX-10
HPLC chromatogram is generated using detection at 280 nm.
|
9,255,143
|
Methods
for Controlling the Galactosylation Profile of Recombinantly-Expressed
Proteins
|
1.
A composition comprising adalimumab, wherein more than 25% of the total
N-linked oligosaccharides present on said adalimumab are of a
galactose-containing fucosylated biantennary oligosaccharide form (sum of
NA1F+NA2F).
|
9,018,361
|
Isolation
and Purification of Antibodies Using Protein A Affinity Chromatography
|
1.
A process for purifying adalimumab from a fermentation harvest of a Chinese
Hamster Ovary (CHO) cell culture expressing said adalimumab, said process
comprising: a) binding adalimumab from said fermentation harvest to a Protein
A resin, b) eluting the bound adalimumab at an elution pH of 3.6-4, and c)
incubating the eluted adalimumab for 1 to 3 hours.
|
[2] Id.
[3]
AbbVie Inc. et al v. Amgen Inc. et al, 1:16-cv-00666 (D. Del).
[4] For the legal implications of
having a Paragraph 5 List that is longer than the paragraph 3 List, see this post: http://biopharmapatent.blogspot.com/2016/09/AbbVie-sues-amgen-over-biosimilar-to.html.
[5] For the reasons as to why the IPR
petition was denied see this post: http://biopharmapatent.blogspot.com/2016/09/institution-of-inter-partes-reviews-ipr.html
[6] AbbVie alleges in its complaint
that “the Patent Office has recognized AbbVie’s innovative work beyond the
invention
of the HUMIRA® antibody itself, granting AbbVie 100 patents, 61 of which are at
issue between the parties.”
