Ex Parte Verkman et al

Patent Trial and Appeal Board

Feb 26, 2019

14402579 (P.T.A.B. Feb. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/402,579 11/20/2014
24504 7590 02/28/2019
THOMAS I HORSTEMEYER, LLP
3200 WINDY HILL ROAD, SE
SUITE 1600E
ATLANTA, GA 30339
FIRST NAMED INVENTOR
Alan S. Verkman
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
290303-1090 2419
EXAMINER
FONTAINHAS, AURORAM
ART UNIT PAPER NUMBER
1649
NOTIFICATION DATE DELIVERY MODE
02/28/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
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ozzie. liggins@tkhr.com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ALAN S. VERKMAN and
LUKMANEE TRADTRANTIP 1
Appeal2018-003252
Application 14/402,579
Technology Center 1600
Before ULRIKE W. JENKS, JOHN G. NEW, and RYAN H. FLAX,
Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants identify The Regents of the University of California as the real
party-in-interest. App. Br. 3.
Appeal2018-003252
Application 14/402,579
SUMMARY
Appellants file this appeal under 35 U.S.C. § I34(a) from the
Examiner's Final Rejection of claims 1, 3-8, 12-14, and 16-19 as
unpatentable under 35 U.S.C. § I03(a) over Budingen, et al. (US
2002/0072588 Al, June 13, 2002) ("Budingen"), J.L. Bennett et al.,
Intrathecal Pathogenic Anti-Aquaporin-4 Antibodies in Early Neuromyelitis
Optica, 66(5) ANN. NEUROL. 617-29 (2009) ("Bennett"), and K.S.
Nandakumar et al., Endoglycosidase Treatment Abrogates IgG
Arthritogenicity: Importance of IgG Glycosylation in Arthritis, 37 EUR. J.
IMMUNOL. 2973-82 (2007) ("Nandakumar").
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to a method of treating neuromyelitis
optica in an animal or human subject comprising administering to the subject
a composition comprising a therapeutically effective amount of an Fe region
modified anti-AQP4 antibody. Abstract.
REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A method of inhibiting or relieving neuromyelitis optica
(NMO) in an animal or human subject comprising administering
to the subject a composition comprising a therapeutically
effective amount of an Fe region modified anti-AQP4 antibody,
wherein the Fe region modified anti-AQP4 antibody is an anti-
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Application 14/402,579
AQP4 antibody deglycosylated at the amino acid position
Asn297, thereby treating the NMO in the subject.
App. Br. 21.
ISSUE AND ANALYSIS
We adopt the Examiner's findings, reasoning, and conclusion that the
claims are prima facie obvious over the combined cited prior art. We
address the arguments raised by Appellants below.
Issue
Appellants argue that the Examiner erred in finding that the combined
cited prior art teaches or suggests the limitations of claim 1. App. Br. 12-
13.
Analysis
The Examiner finds that Budingen teaches a method of treating a
subject with a demyelinating disease comprising administering to the subject
a reagent comprising an autoantibody or an antigen binding fragment that
lacks effector functions (i.e., a functional Fe region) of an intact antibody.
Final Act. 4 (citing Budingen 11-12, 17, 47). The Examiner finds that
Budingen teaches that when Fab antibodies lacking effector function are
administered to a subject with MS, they inhibit binding of the disease-
causing autoantibodies and are therefore efficacious in the treatment of MS.
Id.
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Application 14/402,579
The Examiner finds that Budingen does not teach treating
neuromyelitis optica ("NMO"), which is also a demyelinating disease, or
that the reagent is an antiaquaporin-4 (AQP-4) antibody. Final Act. 4--5.
However, the Examiner finds that Bennett teaches that NMO is
caused by IgG autoantibodies to the aquaporin-4 (AQP-4) protein. Final
Act. 5 (citing Bennett Abstr., 617, 626, 627). The Examiner finds that
Bennett teaches that patients are seropositive for NMO-IgG after NMO
onset. Id. (citing Bennett 618, 627).
The Examiner finds that Bennett teaches that NMO-IgG
autoantibodies mediate tissue injury through both complement-mediated cell
lysis and antibody-dependent cell-mediated cytotoxicity ("ADCC") due to
Fe-mediated effector functions. Final Act. 5 (citing Bennett 623-25). The
Examiner finds that Bennett also teaches that the effector function of IgG
constant region is affected by target epitope of AQP4-specific antibodies.
Id. ( citing Bennett 625). However, the Examiner notes, although Bennett
teaches the use of recombinant anti-AQP4 autoantibodies, Bennett does not
expressly teach using modified anti-AQP4 autoantibodies, with an Fe region
modified by deglycosylation at the amino acid position Asn297 in the
treatment ofNMO. Id.
The Examiner finds that Nandakumar teaches two catabolic enzymes
that are therapeutic in treating IgG-mediated autoimmune disease: IdeS
(also known as Macl) and endo-B-N-acetylglucosaminidase ("EndoS").
Final Act. 6. The Examiner finds that IdeS cleaves the IgG to generate Fe
and F(ab')2 fragments and blocks complement-mediated deposition and Fe-
mediated phagocytosis. Id. (citing Nandakumar 2975). The Examiner
further finds that Nandakumar teaches that the IgG is deglycosylated at
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Application 14/402,579
Asn297 by EndoS, which impairs IgG FcyR binding and decreases
activation of the classical of complement pathway involved in experimental
arthritis induction. Id. at 6-7 (citing Nandakumar 2976-77). The Examiner
also finds that Nandakumar teaches that targeted cleavage of pathogenic
autoantibodies with a rapid and efficient destruction of the antibody's
effector mechanisms would be highly beneficial in treating several types of
disorder and clinical conditions. Id. at 7 (citing Nandakumar 2977).
The Examiner concludes that it would have been prima facie obvious
to a person of ordinary skill in the art to have arrived at the claimed
invention from the disclosures of Budingen, Bennett and Nandakumar.
Final Act. 7. The Examiner also concludes that a skilled artisan would have
had a reasonable expectation of success in combining the references, based
on the cumulative disclosures of the prior art in treating NMO with modified
autoantibodies lacking effector function by competing for the same target as
the autoantibodies found in the patient. Id. at 8.
Appellants argue that Budingen teaches treatment of a non-NMO
autoimmune disease by administering an immunoglobulin CDR3 sequence
derived from combinatorial phage display libraries selected for high-affinity
binding to myelin oligodendrocyte glycoprotein ("MOG"). App. Br. 12
(citing Budingen Abstr., ,r 11). Appellants note that the Examiner
acknowledges that Budingen does not teach NMO, anti-AQP4
autoantibodies, and therefore neither teaches nor suggests treatment ofNMO
with a modified AQP4 or predicts a reasonable expectation of successfully
treating NMO. Id. According to Appellants, the most that Budingen can be
held to teach or suggest is an assertion of a general desire to inhibit
autoantibodies in autoimmune disorders, without providing any express or
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Application 14/402,579
specific direction as to how to apply this to generating a treatment for NMO.
Id.
Appellants contend that Bennett teaches that AQP4 autoantibodies are
involved in the pathogenesis ofNMO, but fails to teach any specific
modification of AQP4 autoantibodies. App. Br. 12. Appellants contend
that, although Bennett teaches identification of antiAQP-4 antibodies in
patients, and the production of at least eleven recombinant anti-AQP4
antibodies, the Examiner acknowledges that Bennett fails to teach or suggest
any modification of the anti-AQP-4 antibodies. Id. Appellants assert that
Bennett focuses on determining the role of the AQP4 autoantibodies in
NMO, rather, Appellants contend, Bennett teaches that the recombinant
AQP4 autoantibodies actually induced NMO pathological effects. Id. ( citing
Bennett 9-10).
Appellants contend that the Examiner cites Nandakumar as teaching
that autoantibodies contribute to the pathology of autoimmune disorders, and
that that removal of autoantibodies would be desirable as a treatment of such
diseases. App. Br. 13. Appellants assert that Nandakumar teaches that IdeS
or EndoS can be administered to a patient with an autoimmune disorder to
treat the autoimmune disorder by reducing the ability of the autoantibody to
have any antibody effector functions. Id. However, argue Appellants,
Nandakumar fails to teach or suggest NMO or AQP4 autoantibodies. Id.
Furthermore, Appellants contend, Nandakumar does not teach specifically
modifying AQP4 antibodies and administering the modified antibodies. Id.
Therefore, Appellants argue that the teachings ofNandakumar, like those of
Budingen, can only reasonably be interpreted as suggesting a general
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Application 14/402,579
approach, but providing no evidence supporting a reasonable of expectation
of success. Id.
Appellants summarize by observing that, at the time of invention, the
prior art taught no more than the general desire to inhibit autoantibodies in
autoimmune disorders, but provides no specific direction as to how to apply
this to generating a treatment for NMO. App. Br. 13 (citing, e.g.,
Budingen). Appellants contend that the general approach of applying IdeS
or EndoS to treat a disease whose pathology may involve autoantibodies, but
not specifically NMO ( citing Nandakumar), and point out that Bennett
teaches that administering non-modified anti-AQP4 antibodies induces,
rather than ameliorates, NMO. Therefore, Appellants conclude, in view of
the cited prior art, it might have been thought logical that Budingen teaches
inhibiting autoantibodies by administering a competing antibody and that
this evidence could be extrapolated to the treatment ofNMO based on the
fact that Bennett teaches that the anti-AQP4 antibodies are involved in the
pathogenesis of the disease. Id. However, Appellants argue, this logic fails,
because Bennett evidences that administration of anti-AQP4 antibodies
actually induces the NMO pathology. Id. As such, Appellants argue, the
combined cited prior art neither teaches nor suggests the selection of the
anti-AQP4 antibodies as a lead compound to be modified in any way,
including with the IdeS or EndoS treatments described in Nandakumar. Id.
We are not persuaded by Appellants' arguments. We agree with
Appellants that, given the findings of the Examiner, it would have been
logical to predict that, because Budingen teaches treating demyelinating
autoimmune diseases (such as NMO) by inhibiting endogenous
autoantibodies via administration of a competing antibody that has an
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Application 14/402,579
immobilized Fe fragment (thus blocking effector function), that this teaching
would have been extrapolated to the treatment ofNMO, based on the fact
that Bennett teaches that the anti-AQP4 antibodies are involved in the
pathogenesis of the disease. See App. Br. 13. However, Appellants contend
that the Examiner's finding that the combination of the references suggests a
way of treating NMO by administration of a competing anti-APQ4
antibodies is undermined by the fact that Bennett teaches that administration
of recombinant anti-AQP4 antibodies results in the development ofNMO
pathogenesis. Id.
Appellants contend, and we do not dispute, that Bennett teaches that:
"[A]dministration of a single AQP4-specific [recombinant antibody] in the
rat MBP EAE model induced an NMO-specific immunopathology:
perivascular astrocyte destruction accompanied by perivascular IgG and
complement deposition" and that "[t ]he experimental results provide the first
definitive evidence that AQP4 autoantibodies in NMO are direct mediators
of disease-specific immunopathology." Bennett 9-10.
However, Appellants overlook Nandakumar's teaching that treatment
of antibodies with EndoS, which deglycosylates the Fe ( effector) fragment at
Asn297, effectively prevents such EndoS-treated antibodies from inducing
symptoms of rheumatoid arthritis, another autoimmune disease, albeit not a
demyelinating autoimmune disorder. Specifically, Nandakumar teaches:
EndoS specifically hydrolyzes the B-1,4-di-N-acetylchitobiose
core of the N-linked glycan ofigG, which can be visualized by a
size difference (4 kDa) on SDS-PAGE and lectin blot analysis
using Lens culinaris agglutinin (LCA).... LCA lectin blot
analysis of the samples revealed a significantly reduced signal
when incubated with EndoS. Loss oflectin signal has previously
been shown to correspond well to the complete digestion of the
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Application 14/402,579
chitobiose core of the glycan on [AS]N297 of human y-chains as
determined by mass spectroscopy.
Nandakumar 2974. 2 Nandakumar thus teaches that EndoS deglycosylates
the Fe fragment of antibodies at Asn297. Importantly, Nandakumar also
teaches that deglycosylation at the Asn297 locus of the Fe effector fragment
essentially blocks the pathogenic effects of autoantibody binding in an
autoimmune disease, rheumatoid arthritis: "As shown[ ... ], there was a
profound inhibition of clinical arthritis in (BALB/c x BIO.Q) Fl and
BIO.RIII mice that had received EndoS-treated Ab." Id. at 2975.
We consequently agree with the Examiner that a person of ordinary
skill in the autoimmune medical art would understand that Nandakumar
teaches that EndoS can be used to deglycosylate the Ans297 locus of the Fe
effector fragment of antibodies, thus inhibiting their ability to induce
parthenogenesis in an autoimmune disease, without effecting the ability of
the autoantibody to its target tissue. See Nandakumar 2975 ("[R]emoval of
carbohydrates by EndoS did not affect the antigen binding capacity of the
mAb"). We also find that a person of ordinary skill in the art would further
understand that EndoS could be employed to similarly inhibit the
autoimmune disease-inducing capability of NM 0-inducing recombinant
2 We note that it was well known in the art at the time of the publication of
Nandakumar that EndoS deglycosylates the Fe fragment of antibodies at
the Asn297 locus. See, e.g., M. Collin et al., EndoS, a Novel Secreted
Protein from Streptococcus pyogenes with Endoglycosidase Activity on
Human IgG, 20(12) EMBO J. 3046-55 (2001) ("Incubation with EndoS,
both in the presence and absence of SpeB, led to a shift of -4 kDa in the
size of the y-chains. This suggested that the glycan moiety on Asn297 was
removed" (internal citations omitted)).
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Application 14/402,579
anti-APQ4 autoantibodies of Bennett, with a reasonable expectation of
success. Moreover, because Nandakumar teaches that EndoS does not
inhibit the binding of autoantibodies to their target tissues, a person of
ordinary skill in the art would understand that EndoS-treated anti-AQP4
recombinant antibodies could be used to competitively inhibit the
development ofNMO by competitively inhibiting endogenous anti-APQ4
antibodies, as per the method taught by Budingen. Specifically, Budingen
teaches that:
In a particular application, the method is a method of inhibiting
demyelination associated with the binding of an autoantibody to
a myelin oligodendrocyte glycoprotein (MOG) polypeptide,
comprising the step of administering to a marmoset or human
host, subject to a pathogenic MOG polypeptide-polyclonal
autoantibody binding, an effective amount of a composition
comprising a subject polypeptide not having a functional Fe
portion and sufficient to specifically bind the MOG polypeptide
and competitively inhibit the binding of the autoantibody to the
MOG polypeptide, whereby the demyelination is inhibited.
Budingen ,r 12 (emphasis added).
Appellants argue, in considerable detail, the differences between the
etiology of the demyelinating disease multiple sclerosis ("MS") and NMO,
contending that a person of ordinary skill in the art would have had no
reasonable expectation of success that the composition of claim 1 would
actually be effective in the treatment ofNMO. See App. Br. 17-18. We are
not persuaded by this argument. The Examiner's primafacie case speaks to
the use of an EndoS-modified AQP4 antibody in inhibiting or relieving
NMO in an animal or human subject. Bennett teaches that the APQ4
antibody is responsible for the induction ofNMO symptoms, and that
Nandakumar teaches a method of essentially "disarming" the Fe fragment of
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Application 14/402,579
autoantibodies at the Asn297 locus. The Examiner concludes, and we agree,
that it would have been obvious to employ such EndoS-treated AQP4
antibodies in the method of competitive inhibition of endogenous
autoantibodies taught by Budingen. We disagree with Appellants'
contention that there could be no reasonable expectation of success in such
an approach. Certainty of success is not the requisite standard, and
Appellants have advanced no plausible argument as to why, given the
Examiner's combination of the references, it would be unreasonable to
expect such a combination to succeed. See In re Langi, 759 F.2d 887, 897
(Fed. Cir. 1985) (holding that: "[ o ]nly a reasonable expectation of success,
not absolute predictability, is necessary for a conclusion of obviousness").
We consequently conclude that the Examiner has established a prima
facie case of obviousness over the combined cited prior art, and we affirm
the Examiner's rejection of the claims.
DECISION
The Examiner's rejection of claims 1, 3-8, 12-14, and 16-19 under
35 U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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