INSTITUTION OF INTER
PARTES REVIEWS (IPR) FOR BIOLOGICAL PATENTS
By:
Payam Moradian on July 27, 2016
A
notable change in recent years in U.S. patent practice has been the institution
of the Inter Partes Review procedure (IPR), which so far has resulted in a high
number of U.S. patents being invalidated by the Patent Trial and Appeal Board
(PTAB). Another recent development has been the Biologics Price Competition and
Innovation Act (BPCIA), under which a biological product may be demonstrated to
be “biosimilar” to an already-approved biological product.
Spurred
by the BPCIA, pharmaceutical companies seeking to market biosimilars have petitioned
the PTAB to institute an IPR for biological patents. An IPR was instituted in approximately half
of the cases pertaining to biological patents (without taking into account
related proceedings/patents) that were reviewed for this article, for an
overall institution rate of approximately 50%.
The approximately 50% institution rate is lower than the 70% institution
rate for all patents.[1] [2]
|
|
IPR2015-01624
Patent 6,331,415
|
IPR2015-00415
Patent 7,820,161
|
IPR2015-00417
Patent 7,976,838
|
IPR2015-01792
Patent 8,163,522
|
IPR2015-00418
Patent 8,329,172
|
IPR2015-01537
Patent 8.476,239
|
IPR2016-00172
Patent 8,889,135
|
IPR2015-01514
Patent 8,916,157
|
|
Instituted
all claims
|
Yes
|
|
Yes
|
|
|
Yes
|
|
|
|
Instituted
Some claims
|
|
Yes
|
|
|
|
|
|
|
|
Not Instituted
|
See
related IPR below
|
|
|
Yes
|
Yes
|
|
Yes
|
Yes
|
|
Secondary considerations accepted
|
|
No
|
No
|
Yes
|
|
|
No
|
|
|
Prior
re-exam
|
Yes
|
|
|
|
|
|
|
|
|
Related IPRs
|
IPR2016-00460
IPR2016-00383
(Not
Instituted)
IPR2016-00710
|
IPR2015-01744
|
IPR2015-01733
|
|
|
|
IPR2016-00408
IPR2016-00409
(IPR2016-00189
Patent
9,073,987)
(IPR2016-00188
Patent
9,017,680)
|
IPR2015-01517
Patent
8,916,158
(Not
Instituted)
|
In the
first instance[3]
where an IPR was not instituted, the claimed formulation was to a stabilized liquid
antibody formulation:
1. A stable
liquid aqueous pharmaceutical formulation
comprising
(a) a human
IgG1[1] 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.
[4]The
petitioner cited to a prior art antibody formulation that was lyophilized and
not stable when combined with water, or low-concentration (10 mg/ml or less)
liquid formulations.[5] The patent holder argued that the prior art
cited by the petitioner pointed to the unpredictability of making suitable
stabilized formulations of antibodies, to the extent that the petitioner had
relied on the same prior art as evidence of unpredictability in the art during
prosecution of petitioner’s own protein formulation patent applications.[6] Agreeing with the patent holder, the PTAB did
not institute an IPR since “the prior art [did not provide] sufficient guidance
such that a skilled artisan would have had a reasonable expectation of success
in arriving at the formulation of stable, liquid pharmaceutical compositions
comprising antibodies at a concentration of 20 to 150 mg/ml.”[7]
In
the second instance where an IPR was not instituted, the claim of the patent was
directed to a method for making a fusion protein of a TNF receptor with all the
domains of the constant region of an antibody “other than the first domain of
said constant region:”
1. A method
comprising the steps of:
(a) culturing a
host cell comprising a polynucleotide, wherein the polynucleotide encodes a
protein consisting of:
(i) the extracellular region of an
insoluble human TNF receptor, wherein the insoluble human TNF receptor has an apparent
molecular weight of about 75 kilodaltons as determined on a non-reducing
SDS-polyacrylamide gel and comprises the amino acid sequence
LPAQVAFXPYAPEPGSTC
(SEQ ID NO: 10), and
(ii) all of the domains of the constant region of a human IgG immunoglobulin
heavy chain other than the first domain of said constant region, and
(b) purifying an
expression product of the polynucleotide from the cell mass or the culture
medium.
(emphasis added) [8] [9] The “Patent Owner offered expert testimony as
to the unexpected results of improved TNF binding affinity, potency, kinetic
stability, and reduced antibody effector function and aggregation ability.”[10] According to the PTAB, the prior art did “not
point to selective deletion of the CH1 domain to achieve any enhanced binding
affinity.”[11]
In
the third instance where an IPR was not instituted, the patent claimed a method
of treating low grade B-cell non-Hodgkin’s lymphoma (NHL):
A method of treating low grade B-cell non-Hodgkin’s lymphoma
in a human patient comprising administering to the patient chemotherapy
consisting of CVP therapy to which the patient responds, followed by rituximab
maintenance therapy, wherein the maintenance therapy comprises four weekly
administrations of rituximab at a dose of 375 mg/m2 every 6 months,
and wherein the maintenance therapy is provided for 2 years.
[12]
[13] The PTAB found that the prior art relied on
by the petitioner differed in at least three respects: by treating patients
with intermediate grade NHL (IG-NHL), rather than the low grade NHL (LG-NHL), not
teaching rituximab maintenance therapy following CVP induction therapy, and being
silent as to the dosing for maintenance therapy.
In
the fourth instance, the PTAB did not institute an IPR against some of the
claims of a patent based on two separate grounds.[14] The first ground[15]
was that the prior art did not teach “administer[ing] more than one intravenous
dose of a therapeutically effective amount of rituximab in combination with the
corticosteroid-methotrexate combination.”[16] The second ground[17]
was that the prior art did not teach “administering an initial dose of the
rituximab followed by a subsequent dose, where the mg/m2 dose of the
rituximab in the subsequent dose exceeds the mg/m2 dose of the
rituximab in the initial dose.”[18]
Interestingly,
the PTAB decided to institute an IPR in one proceeding against Genentech’s
Cabilly patent (which claims expression of a light and a heavy chain of an
antibody separately in a single host cell), stating that the prior art
“suggests the incorporation of a plurality of structural genes encoding for the
subunits of a multimeric protein, such as immunoglobulin heavy and light
chains, within a vector that would be placed in a single host cell,”[19]
while in another IPR, the PTAB did not institute an IPR against the same
patent, stating that “[n]either Petitioner nor its expert explain how the
ordinary artisan would envision the expression of an immunoglobulin heavy and
light chain DNA sequences after reading Salser disclosure of the beta-globin
gene cluster, which results in the expression of five separate polypeptides at
different times.”[20] The PTAB’s opposite decisions regarding the
same patent signify the importance of choosing the correct prior art for an IPR
petition, and that PTAB’s refusal to institute IPR based on one set of prior
art does not necessarily bar it from instituting an IPR based on another set of
prior art.
Regardless
of the above refusals to institute an IPR, the PTAB has generally held different
dosages and formulations to be obvious in instituting several IPRs. For example, in one IPR,[21]
the PTAB found each of the following limitations for an antibody formulation to
be taught or suggested by the prior art:
[1] at
least 100mg/ml CTLA4Ig molecule,
[2] a sugar
selected from the group consisting of sucrose, lactose, maltose, mannitol and
trehalose and mixtures thereof and
[3] a
pharmaceutically acceptable aqueous carrier, wherein the formulation has a
[4] pH range of
from 6 to 8 and
[5] a viscosity
of from 9 to 20 cps, and
[6] the weight
ratio of sugar:protein is 1.1:1 or higher.
The PTAB rationalized that since the prior art “teaches
a specific dosage of CTLA4Ig . . . it is reasonably likely that those of
ordinary skill in the art would have been able to determine an effective
concentration for a subcutaneously administered formulation from that dosage.”[22]
With
biosimilars, there is often a successful blockbuster drug that a patent owner
tries to rely on for a showing of secondary considerations, particularly
commercial success. However, on three
separate occasions the PTAB has dismissed the patent holder’s alleged secondary
considerations based on a blockbuster drug. In one IPR where the claim of the patent was
“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,”
the PTAB found the commercial success of the drug HUMIRA® not to be
commensurate with the scope of the claimed invention:
The record before us at this time, however,
indicates that the commercial success of HUMIRA® is not commensurate
in scope with the claimed invention—40 mg subcutaneous, every-other week
administration to treat RA. For example, although the evidence Patent Owner
presents attributes the overall sales of HUMIRA® in part to
subcutaneous, biweekly flat dosing, there appears to be little indication that
sales are due to the 40 mg dose amount recited in the claims.
Moreover, evidence cited by Patent Owner also
attributes overall sales of HUMIRA® to the fully human D2E7
anti-TNFα antibody, which was known in the prior art. Patent Owner’s evidence
further indicates that HUMIRA® has been FDA-approved and “has
enjoyed success” in treating autoimmune diseases other than the recited RA,
such as psoriatic arthritis, and intestinal disorders, such as Crohn’s disease,
since October 2005 and February 2007, respectively. Accordingly, at this stage
of the proceeding, the arguments and information of record do not persuade us
to decline to go forward with a trial.
[23]Yet
in another IPR, where the claim was to “a method of treating rheumatoid
arthritis,” the PTAB dismissed the commercial success of the drug rituximab
since the patent owner could not precisely determine the sales split between RITUXAN®
use in oncology and immunology settings:
Patent Owner asserts that the claimed methods have
led to significant commercial success, based on worldwide sales of
rituximab. The overall sales, however,
are described as being attributable to the use of rituximab in oncology, e.g.,
to treat non-Hodgkin’s lymphoma, as well as to its use in immunology. (“It remains difficult to precisely
determine the sales split between Rituxan use in oncology and immunology
settings.”). As such, Patent Owner has failed, on the current record, to
establish sufficient nexus between the commercial success of the product and
any element recited in the claims.
[24] Reliance on RITUXAN® for secondary
considerations was also dismissed by the PTAB for a patent in which the claim
recited a method of treating rheumatoid arthritis in a human with the
combination of rituximab and methotrexate, with the PTAB taking the position
that the result of the claimed method was not unexpected compared with the
closest prior art:
Patent Owner also asserts that the
claimed treatment methods produce unexpected results. In support of this
assertion, Patent Owner refers to the Edwards 2004 study demonstrating that
“the claimed combination of rituximab with methotrexate provided greater
therapeutic effects than rituximab alone in patients who ‘had active rheumatoid
arthritis despite [prior] treatment with methotrexate.” The conclusions of the
study, however, were that significant improvement in disease symptoms were
observed in patients administered rituximab “alone or in combination with
either cyclophosphamide or continued methotrexate.” In other words, in all
groups treated with rituximab, alone or in combination, significant improvement
in disease symptoms occurred. Patent Owner has not explained sufficiently how
these results establish that the results of the claimed method were unexpected
compared with the closest prior art.
[25]In
the IPR in which the PTAB accepted the secondary considerations, the secondary consideration
was improved binding affinity and other properties resulting from fusion of a
TNF receptor to an antibody constant region lacking the first domain of the
constant region.[26] In denying the petition to institute an IPR,
the PTAB noted that the petitioner had not addressed the secondary
considerations that the patent holder had relied on before the Patent Office
during prosecution to obtain the patent:
During the prosecution of the ’522 patent, Patent
Owner offered expert testimony concerning the unexpected results of improved
TNF binding affinity, potency, kinetic stability, and reduced antibody effect or
function and aggregation ability. We
agree with Patent Owner that the unrebutted objective indicia of nonobviousness
presented in the prosecution history of the ’522 patent, and apparently relied
upon by the Examiner, at least in part, in allowing the claims of the ’522
patent, see Ex. 1026, 6, supports the nonobviousness of the challenged claims.
The Petition, moreover, should have addressed the evidence of unexpected
results as part of Petitioner’s showing of a reasonable likelihood of success
on the merits.
[27]The
PTAB’s refusal to institute an IPR in this case underlies the importance of
addressing in an IPR petition any secondary considerations relied on by a patent
holder during prosecution.
The
PTAB seems to exercise its discretion in instituting an IPR despite prior
proceedings in which similar issues were raised. Notably the PTAB instituted an IPR against
Genentech’s Cabilly patent. The PTAB
instituted the IPR regardless of the past reexamination proceeding since “the
particular combination of references upon which we institute were not
previously addressed during prosecution or reexamination.”[28] In other instances, the PTAB instituted IPRs
despite the same arguments being raised in prosecution of the same or related
application.[29]
In
summary, an IPR was instituted in approximately half of the cases (without
taking into account related proceedings/patents). A patent holder’s reliance on secondary
considerations based on the sales of a blockbuster drug or decisions in prior
proceedings seem not to be a factor in PTAB’s decision to institute an
IPR. The PTAB seems to give weigh to secondary
considerations relied on during prosecution and evidence as to unpredictability
in the prior art relating to biologic inventions. The PTAB also scrutinizes in great detail
alleged prior teachings in the prior art set out by a petitioner.
[1]
<https://www.rpxcorp.com/2015/10/19/rising-and-falling-iprs-at-institution/>
Accessed June 30, 2016.
[2] In addition to these IPRs, there
is a pending IPR (IPR2016-01018) petition for U.S. Patent 9,114,166, which the
PTAB has not yet made a decision on.
Related IPRs have been grouped together.
[3] IPR2015-01514.
[4] Id., Paper No. 9, at 3.
[5] Id. at 13.
[6] Id. at 14.
[7] Id.
[8] IPR2015-01792, Paper No. 14, at 3.
[9] The PTAB construed “all of the
domains of the constant region of a human IgG immunoglobulin heavy chain other
than the first domain of said constant region” to mean “‘-hinge-CH2-CH3’ region
of a human IgG immunoglobulin
heavy
chain,” and “all of the domains of the constant region of a human IgG1
immunoglobulin heavy chain other than the first domain of said constant region”
to mean “’-hinge-CH2-CH3’ region of a human IgG1
immunoglobulin
heavy chain.” Id. at 7.
[11] Id. at 17.
[12] IPR2015-00418, Paper No. 14, at
4.
[13] CVP therapy is a combination of
the drugs cyclophosphamide, vincristine, and prednisone, which is sometimes
referred to as “COP” because the drug vincristine is also known as oncovin.
[14] IPR2015-00415.
[15] For dependent claims 3, 7, and
11.
[16] Id., Paper No. 13, at 25.
[17] For dependent claims 4, 8, and
12.
[18]
Id. at 26.
[19] IPR2015-01624, Paper No. 15, at
18-19.
[20] IPR2016-00383, Paper No. 16, at
19.
[21] IPR2015-01537
[22] Id., at 10.
[23] IPR2016-00172, Paper No. 9, at
21-22.
[24] IPR2015-00417,
Paper No. 11, at 25.
[25] IPR2015-00415, Paper No. 13, at
28-29.
[26] IPR2015-01792,
Paper No. 14, at 18.
[27] Id.
[28] IPR2015-01624, Paper No. 15, at
24.
[29] IPR2016-00172, Paper No. 9,
at10.
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