Ex Parte Saus et al

Patent Trial and Appeal Board

Mar 29, 2017

13400831 (P.T.A.B. Mar. 29, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/400,831 02/21/2012 Juan Saus 11-365-US 1094
20306 7590 03/29/2017
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EXAMINER
300 S. WACKER DRIVE HADDAD, MAHER M
3 2ND FLOOR
CHICAGO, IL 60606 ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
03/29/2017 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JUAN SAUS, FERNANDO REVERT,
RAMON MERINO, JESUS MERINO,
and FRANCISCO REVERT-ROS1
Appeal 2015-006665
Application 13/400,831
Technology Center 1600
Before RICHARD M. LEBOVITZ, JOHN G. NEW, and TIMOTHY G.
MAJORS, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants state the real party-in-interest is FibroStatin S.L. App. Br. 3.
Appeal 2015-006665
Application 13/400,831
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Non-Final Rejection of claims 4, 5 and 20—30 which stand
rejected as unpatentable under 35 U.S.C. § 103(a) as being obvious over the
combination of F. Revert et al., Increased Goodpasture Antigen-Binding
Protein Expression Induces Type IV Collagen Disorganization and Deposit
of Immunoglobulin A in Glomerular Basement Membrane, 171(5) Am. J.
Pathol. 1419-30 (2007) (“Revert 2007”), F. Revert et al., Goodpasture
Antigen-binding Protein Is a Soluble Exportable Protein That Interacts with
Type IV Collagen: Identification of Novel Membrane-Bound Isoforms,
283(44) J. Biol. Chem. 30246-55 (2008) (“Revert 2008”), Saus et al. (US
2010/0021935 Al, January 28, 2010) (“Saus ’935”), and F. Bard et al.,
Peripherally Administered Antibodies against Amyloid B-Peptide Enter the
Central Nervous System and Reduce Pathology in a Mouse Model of
Alzheimer Disease, 6(5) Nature Medicine 916-19 (2000) (“Bard”).2
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
2 The Examiner also rejected claims 4, 5 and 20—30 as unpatentable under 35
U.S.C. § 103(a) as being obvious over Saus ’935 and T. Miralem et al.,
Human Biliverdin Reductase Suppresses Goodpasture Antigen-binding
Protein (GPBP) Kinase Activity: The Reductase Regulates Tumor Necrosis
Factor-a-Nf-Kb-Dependent GPBP Expression, 285(17) J. BIOF. CHEM.
12551-58 (2010). Although Appellants argue this rejection in their Appeal
Brief, the Examiner has withdrawn the rejection. See Non-Final Act. 11;
Ans. 2.
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NATURE OF THE CLAIMED INVENTION
Appellants’ invention is directed to methods for the diagnosis and/or
treatment of chronic kidney disease, immune complex-mediated
glomeralamephritis (“IC-GN”), rheumatoid arthritis, and pulmonary
fibrosis, and methods for identifying compounds for such therapeutic use.
Abstract.
GROUPING OF CLAIMS
Appellants argue all claims together. Claim 4 is representative and
recites:
4. A method for treating immune complex-mediated
glomerulonephritis (GN), comprising administering to a subject
in need thereof an amount effective of an antibody that binds to
circulating 77 kD Goodpasture antigen binding protein (GPBP)
to treat the immune complex-mediated GN.
App. Br. 17.
ISSUE AND ANALYSIS
We agree with, and adopt, the Examiner’s findings of fact, reasoning,
and conclusion that the claims would have been obvious over the cited prior
art references. We address Appellants’ arguments below.
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A. Rejection of the claims over Revert 2007, Revert 2008, Saus ’935, and
Bard
Issue
Appellants argue the Examiner erred in finding the combined cited
prior art references teach or suggest the limitations of claim 4 reciting:
(1) “a method for treating immune complex-mediated glomerulonephritis
(GN)”; (2) “administering to a subject... an antibody ... to treat the immune
complex-mediated GN”; and (3) wherein the administered antibody “binds
to circulating 77 kD Goodpasture antigen binding protein (GPBP).” App.
Br. 6.
Analysis
Appellants argue the Examiner acknowledges that neither Revert 2007
nor Revert 2008 teaches or suggests any methods for treating immune
complex-mediated GN (“IC-GN”), or any methods comprising
administering antibodies of any kind to a subject, let alone antibodies that
bind to circulating GPBP (“cGPBP”). App. Br. 6—7. Specifically,
Appellants argue Revert 2007 neither teaches nor suggests methods of
treating GN, nor does Revert 2007 disclose administration of antibodies to a
subject, by which the antibodies bind circulating GPBP. Id. Rather,
Appellants contend, the Examiner instead finds Revert 2007 teaches that “m
vivo GPBP regulates type IV collagen organization and elevated expression
of [ ] kinase induces immune complex-mediated glomerulonephritis.” Id. at
7 (quoting Non-Final Act. 3 (citing Revert 2007 1420)).
Appellants argue that, similarly, the Examiner finds that Revert 2008
teaches “Goodpasture antigen-binding protein is a soluble exportable protein
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that interacts with type IV collagen .... Revert et al teach that the 77-kDa
GPBP is mainly found in the extracellular compartment both soluble (Fig. 5)
or associated with glomerular basement membrane collagen.” Id. (quoting
Non-Final Act. 3 (citing Revert 2008 30254). However, Appellants argue,
Revert 2008 contains no teaching or suggestion regarding the treatment of
IC-GN by administering anti-cGPBP antibodies, as recited in claim 4. Id.
With respect to Saus ’935, Appellants contend the Examiner has
mischaracterized the teachings of the reference. App. Br. 7. According to
Appellants, Saus ’935 does not, in fact, teach that anti-GPBP antibodies
would make useful therapeutics. Id. at 7—8. Appellants point to paragraph
[0071] of Saus ’935, which recites:
The polypeptides [91 kD GPBP and 77 kD GPBP] of this aspect
of the invention can be used, for example, to produce antibodies
against native GPBP forms, and as targets for identification of
compounds that interfere with native GPBP activity, making
them useful therapeutics for various disorders, including
Goodpasture Syndrome.
(emphases added by Appellants). Appellants contend that the pronoun
“them,” when read in the context of the passage as a whole, refers back to
“the polypeptides,” rather than to the “antibodies.” Id. at 8. Therefore,
argue Appellants, Saus ’935 does not teach GPBP-binding antibodies that
“mak[e] the antibodies useful therapeutics for various disorders,” as found
by the Examiner. Id.
Appellants next point to the Declaration of Dr. Juan Saus (the “Saus
Declaration”), one of the co-inventors of the present application. App. Br. 8.
Appellants point to paragraph 8 of the Saus Declaration as stating:
The ’935 application teaches the existence of circulating GPBP
(cGPBP) which is also referred to as circulating 77 kD GPBP, and
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that cGPBP is a biomarker for diagnosing IC-GN. The ‘935
application does not disclose that cGPBP/77 kD GPBP, in
addition to being a biomarker for the diagnosis of IC-GN, is
also a therapeutic target for the treatment of IC-GN, as
recited in the instant claims.
Id. (emphasis added by Appellants).
With respect to the teachings of Bard, Appellants contend Bard
contains no teaching or suggestion of IC-GN, GPBP, or anti-GPBP
antibodies. App. Br. 9.
The Examiner responds that, first, Appellants are impermissibly
attacking the references singly, when the Examiner relied upon the
combined teachings and suggestions of the references. Ans. 6 (citing, e.g.,
In re Keller, 642 F.2d 413, 426 (C.C.P.A. 1981).
The Examiner finds Appellants’ claimed invention differs from
teachings and suggestions of Revert 2007 and Revert 2008 only in the
recitation of a method for treating immune complex-mediated
glomerulonephritis with administration of anti-cGPBP antibody. Non-Final
Act. 4.
Specifically, the Examiner finds Revert 2007 teaches that increased
expression of GPBP, a protein that binds and phosphorylates basement
membrane collagen in the renal glomerulus, has been associated with
immune complex-mediated pathogenesis and that New Zealand White
(“NZW”) mice develop age-dependent lupus-prone autoimmune response
and IC-GM characterized by elevated GPBP, glomerular basement
membrane (GBM) collagen disorganization and expansion and deposits of
IgA on disrupted GBM. Non-Final Act. 2. The Examiner finds Revert 2007
provides in vivo evidence that GPBP regulates GBM collagen organization
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and its elevated expression causes dissociation and subsequent accumulation
of IgA on the GBM. Id. at 2—3. The Examiner also finds Revert 2007
teaches a previously unrecognized pathogenic mechanism that may be
relevant in human primary immune complex-mediated glomerulonephritis.
Id. at 3 (citing Revert 2007 Abstr., 1423 and 1426).
The Examiner further finds Revert 2008 teaches GPBP is a soluble
exportable protein that interacts with type IV collagen. Non-Final Act. 3.
The Examiner finds cells express at least two GPBP isoforms resulting from
canonical (77-kDa) and noncanonical (91-kDa) mRNA translation initiation:
the 77-kDa polypeptide interacts with type IV collagen and localized as a
soluble form in the extracellular compartment. Id. The Examiner also finds
Revert 2008 teaches that the 77-kDa GPBP is mainly found in the
extracellular compartment in soluble form or associated with glomerular
basement membrane collagen. Id. at 4 (citing Revert 2008 30254). The
Examiner also finds Revert 2008 teaches that various lines of evidence
support that COL4A3BP (i.e., the gene which encodes GPBP) is an
attractive target for strategies to treat antibody-mediated disorders which
discriminate between different gene products (i.e., GPBP and
GPBPA26/CERT), which are expressed at distinct cell compartments and
are differentially regulated in response to stimuli. Id. at 3^4 (citing Revert
2008 30255).
With respect to Saus ’935, the Examiner finds that, in paragraph
[0071] of the reference quoted supra, the pronoun “them” refers to the
antibodies and the compounds that interfere with native GPBP activities.
Ans. 6—7. The Examiner points to paragraph [0003] of Saus ’935, which
recites: “The identification of GPBP provided methods for identification of
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compounds for the treatment of autoimmune disorders, cancer, protein
misfolding-mediated disorders and aberrant apoptosis, and also provided
potential therapeutics for these disorders.” Id. at 7. The Examiner also
points to paragraph [0062] of Saus ’935, which recites: “The polypeptides of
the invention can also be used, for example, as tools to identify candidate
compounds for inhibiting various specific types of native GPBP isoforms
and also to identify candidate compounds for treating, for example,
autoimmunity and protein misfolding-mediated disorders, as discussed in
more detail below.” Id. The Examiner also finds Saus ’935 teaches:
“Various lines of evidence support that COL4A3BP is an attractive target for
strategies to diagnose and treat antibody-mediated disorders.” Id. (citing
Saus ’935 1 179).
The Examiner also finds that Saus ’935 teaches:
[B]y identifying circulating human 77-kDa GPBP, we provide
compelling evidence that GPBP secretion is also biologically
relevant in vivo. The finding that the levels of circulating 77-kDa
GPBP correlate with GPBP glomerular expression and
pathogenesis in mouse models of immune complex-mediated
glomerulonephritis suggests that serological determination of
GPBP is relevant in a clinical setting. Consistent with this,
present studies demonstrating upregulation of circulating GPBP
in Goodpasture patients support these conclusions and
substantiate previous observations that GPBP is overexpressed in
these patients.
Ans. 9—10 (citing Saus ’935 1180). The Examiner consequently finds that a
person of ordinary skill in the art would be motivated to target the
circulating 77-kDa GPBP with an anti-77-kDa cGPBP antibody to combat
IC-GN because the anti-cGPBP antibody suggested by Saus ’935 would
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appear to be compatible with physiological use and is not incompatible with
a therapeutic intention. Id. at 10.
With respect to Appellants’ argument concerning the teachings of
Bard, the Examiner finds Bard teaches:
[TJransgenic overexpressing Ap (PDAPP mice) [sic] show many
of the pathological features of Alzheimer disease, including
extensive deposition of extracellular amyloid plaques,
astrocytosis and neuritic dystrophy. Bard et al demonstrated that
intraperitoneal administration of anti-Ap antibodies in transgenic
mice overexpressing AB lead to brain Ap plaque clearance.
Ans. 10 (quoting Non-Final Act. 5).
The Examiner finds Bard thus teaches a “proof-of-concepf ’ for using
antibodies against an elevated level of a specific protein in transgenic mice
overexpressing that specific protein, which results in the development of, or
predisposition to, various disease states, as an effective method to diminish
the disease state. Ans. 11. Specifically, the Examiner finds Bard teaches a
successful method of treatment of transgenic mice overexpressing a disease-
linked protein by administering antibodies to that protein, and would lead a
person of ordinary skill in the art made to combine the method taught by
Bard with Revert 2007 and Revert 2008 to solve a similar problem with
respect to IC-GN. Id.
We are not persuaded by Appellants’ arguments. As an initial matter,
we agree with the Examiner that Appellants “cannot show non-obviousness
by attacking references individually where ... the rejections are based on
combinations of references.” Keller, 642 F.2d 413.
The gravamen of Appellants’ argument is that none of the references,
Revert 2007, Revert 2008, and Saus ’935, teach the treatment of IC-GN by
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administering anti-cGPBP antibodies, as recited in claim 4. App. Br. 7—9.
Nevertheless, it is not disputed by Appellants that Revert 2007 and Revert
2008, as well as Saus ’935, teach that elevated levels of cGPBP are directly
involved in the etiology of, and is a biomarker for, IC-GN. Id. With respect
to whether, in paragraph [0071] of Saus ’935, the pronoun “them” refers to
the GPBP polypeptides or antibodies directed against those polypeptides, we
agree with Appellants that a plain reading of the passage reveals that “them”
refers to the recited polypeptides rather than the antibodies. But we are not
persuaded that this evidences that claim 4 would have been nonobvious.
Rather, we find that a person of ordinary skill in this sophisticated art would
understand that the identification of elevated levels of a circulating
polypeptide directly implicated in the mechanism of IC-GN would be a
natural target against which to direct immobilizing antibodies, as suggested
both by paragraph [0071] of Saus (“this aspect of the invention can be used,
for example, to produce antibodies against native GPBP forms”) as well as
the teachings of Bard cited by the Examiner. We consequently agree with
the Examiner that Saus ’935’s teaching of antibodies directed against the 77-
kDacGPBP proteins in view of the known utility of antibodies in treating
disease as taught by Bard would be an obvious, significant and promising
direction in the development of therapies for the treatment of IC-GN.
Finally, we agree with the Examiner that Bard, although not directed
to IC-GN, would suggest to a person of ordinary skill in the art that
antibodies directed against elevated levels of a circulating protein believed
to be involved in the mechanism of a disease (Alzheimer’s disease, in the
case of Bard) and would suggest that the use of antibodies directed against
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circulating, disease-associated proteins as an effective mechanism of treating
the polypeptide-associated disease by immobilizing the proteins.
B. Reasonable Expectation of Success
Issue
Appellants next argue the Examiner erred because a person of
ordinary skill at the time of filing would not have had a reasonable
expectation of success in combining the references. App. Br. 9.
Analysis
Appellants point to the Saus Declaration, which opines:
In fact one of skill in the art would expect that cGPBP-specific
antibody treatment would not be effective to treat IC-GN. GPBP
causes basement membrane collagen misfolding, which is
expected to be accomplished inside the cell at the reticulum
endoplasmic where basement membrane collagen assembles and
antibodies cannot penetrate in this cellular compartment. The
’935 application discloses that increased cellular expression of
GPBP is associated with increased levels of cGPBP and therefore
extracellular cGPBP is a biomarker for monitoring what is
occurring inside the cell. However, one of skill in the art would
find it non-obvious and unexpected that blocking extracellular
cGPBP would have consequences on any deleterious effects of
intracellular GPBP, such as its basement membrane collagen
misfolding and IC-GN, since there is no known positive feedback
operating between extracellular (cGPBP) and intracellular
(GPBP).
App. Br. 10 (emphasis omitted) (quoting Saus Deck 19). Appellants
therefore argue that there was nothing in the art at the time of filing to
indicate that blocking circulating (extracellular) GPBP, as recited in
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Applicants’ claims, would have any effect on intracellular GPBP, the latter
of which is likely involved in IC-GN pathogenesis. Id. Therefore,
Appellants contend, IC-GN is likely associated with the deleterious effects
of intracellular GPBP, and the teachings of Revert 2008 — that circulating
77-kDa GPBP is mainly found extracellularly but not intracellularly —
would have undermined a person of ordinary skill’s expectation of success
in treating IC-GN by targeting extracellular GPBP. Id. at 11—12.
Appellants next point to paragraph [0179] of Saus ’935 and Revert
2008 at page 30255, both of which recite:
Various lines of evidence support that COL4A3BP is an attractive
target for strategies to diagnose and treat antibody-mediated
disorders, inflammation, ER stress-mediated diseases and drug
resistant cancer. However, observations supporting these
conclusions may now need to be re-interpreted since many
have been obtained using tools (i.e. siRNA or antibodies) which
failed to discriminate between different gene products (i.e. GPBP
and GPBPA26/ACERT), that are expressed at distinct cell
compartments, and are differentially regulated in response to
stimuli.
App. Br. 11 (emphases added by Appellants). Appellants assert this
paragraph refers to antibody-mediated disorders, and not to antibody-based
therapies. Id. Therefore, Appellants contend, this teaching provides no
instruction whatsoever regarding using anti-COL4A3BP antibodies to treat
IC-GN; a disease that is not even mentioned in paragraph [0179]. Id.
Furthermore, Appellants note, the quoted paragraph states that “these
conclusions may now need to be re-interpreted, suggesting that COL4A3BP
may not, in fact, be an attractive target or suggest a reasonable expectation
of success. App. Br. 11.
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The Examiner responds that Revert 2007 teaches that transgenic
overexpression of human GPBP (hGPBP) in non-lupus-prone mice triggered
similar glomerular abnormalities including deposits of IgA on a capillary
glomerular basement membrane (“GBM”) that underwent dissociation, in
the absence of an evident autoimmune response. Ans. 12. The Examiner
finds Revert 2007 provides in vivo evidence that GPBP regulates GBM
collagen organization, and elevated expression of GPBP causes dissociation
and subsequent accumulation of IgA on the GBM. Id.
The Examiner finds Revert 2007 describes a previously unrecognized
pathogenic mechanism that may be relevant in human primary immune
complex-mediated glomerulonephritis. Id. at 12—13 (citing Revert 2007
Abstr., 1423). The Examiner finds the teachings of Revert 2007 provide
evidence that in vivo GPBP regulates type IV collagen organization and
elevated expression of this kinase induces immune complex-mediated
glomerulonephritis. Id. at 13 (citing Revert 2007 1420). The Examiner
further finds Revert 2007 also teaches that their glomerulonephritis mouse
models share the triad of elevated GPBP expression, type IV collagen
alterations, and IgA deposit formation and autoimmune responses in Tg-
hGPBP mice, including presence of anti-GBM autoantibodies, suggests that
antibody binding to disrupted GBM occurs through an antigen-antibody-
independent mechanism. Id. (citing Revert 2007 1429). The Examiner
finds, however, that Revert 2007 teaches that Tg-hGPBP mice display less
severe glomerular lesions than NZW mice, suggesting that autoantibodies
are a contributing pathogenic factor in NZW mouse glomerulonephritis. Id.
(citing Revert 2007 1429).
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The Examiner further finds that Revert 2008 teaches that the
cGPBP/77-kDa GPBP is mainly found in the extracellular compartment both
as a soluble protein soluble and associated with glomerular basement
membrane collagen. Ans. 14 (citing Revert 2008 30254). Importantly, the
Examiner finds, Revert teaches that various lines of evidence support the
conclusion that COL4A3BP (i.e., GPBP gene) is an attractive target for
strategies to treat antibody-mediated disorders which discriminate between
different gene products (i.e., GPBP and GPBPA26/CERT), which are
expressed in distinct cell compartments and are differentially regulated in
response to stimuli. Id. (citing Revert 2008 30255). The Examiner also
finds Revert 2008 teaches that GPBP phosphorylates the NCI domain of the
a3(IV))NCl which is a pivotal structure in the molecular and
supramolecular organization of the glomerular basement membrane collagen
and also the target of autoantibodies mediating glomerulonephritis in
Goodpasture diseases. Id. The Examiner finds Revert 2008 thus teaches
GPBP regulates glomerular basement membrane collagen organization and
induces type IV collagen-based, antibody-mediated glomerulonephritis when
its expression is abnormally elevated. Id. (citing Revert 2008 30246).
The Examiner finds the Saus Declaration is insufficient to overcome
the Examiner’s rejection because the anti-cGPBP antibodies would reach
those 77-kDaGPBP associated with glomerular basement membrane
collagen in the IC-GN treatment. Ans. 14—15. The Examiner further finds
Saus ’935 provides an explicit suggestion that antibodies that binds to the
native 77-kDaGPBP (cGPBP) polypeptide would be useful therapeutic
agents for various disorders, including Goodpasture syndrome. Id. at 14—15
(citing Saus ’935 171).
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With respect to Dr. Saus’ opinion regarding misfolding at the
endoplasmic reticulum, and the antibodies’ lack of ability to penetrate the
cellular compartment, the Examiner finds the opinion is not relevant because
the anti-GPBP antibodies target the circulating/soluble 77-kDacGPBPs, and
not the 91-kDa GPBPs present in the cellular compartments. Ans. 15. The
Examiner finds a person of ordinary skill in the art would have been
specifically motivated to target the cGPBP isoform in the treatment of IC-
GN, because administering the anti-cGPBP antibody would discriminate
between the different GPBP isoforms and would neutralize only the
interaction between cGPBP and the type IV collagen complex and prevent
the type IV collagen-based antibody-mediated glomerulonephritis. Id.
Finally, the Examiner finds both Saus ’935 and Revert 2008 clarify
the mechanisms by which various isoforms of GPBP are generated within
the cells. Ans. 18. The Examiner finds Saus ’935 teaches that
Identification of the circulating human 77-kDa GPBP provides compelling
evidence that GPBP secretion is biologically relevant in vivo. Id. The
Examiner finds Saus ’935 teaches that levels of circulating 77-kDa
GPBP correlate with GPBP glomerular expression and pathogenesis in
mouse models of immune complex-mediated glomerulonephritis, and
suggests that serological determination of GPBP is relevant in a clinical
setting. Id. The Examiner also finds Saus ’935 teaches that upregulation of
circulating GPBP in Goodpasture patients support these conclusions and
substantiate previous observations that GPBP is overexpressed in such
patients. Id. (citing Saus ’935 1180).
The Examiner finds Revert 2008 teaches that the 77-kDa cGPBP
interacts with type IV collagen and can be localized in its soluble form in the
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extracellular space. Id. (citing Revert 2008 Abstr.). The Examiner finds
Revert 2008 teaches the 77-kDaGPBP phosphorylates the NCI domain of
the a3(IV))NCl which is a pivotal structure in the molecular and
supramolecular organization of the glomerular basement membrane collagen
and also the target of autoantibodies mediating glomerulonephritis in
Goodpasture diseases. Id. The Examiner finds Revert 2008 teaches 77-kDa
cGPBP regulates glomerular basement membrane collagen organization and
induces type IV collagen-based antibody-mediated glomerulonephritis when
its expression is abnormally elevated and that an increased expression of the
77-kDa cGPBP perturbs the quaternary structure of type IV collagen,
suggesting that the elevated cGPBP levels interfere with the conformational
diversification program (tertiary structure) of the a3(IV)NCl domain. Id.
(citing Revert 2008 30246, 30254—55).
We are not persuaded by Appellants’ arguments. Appellants rely
upon the Saus Declaration to argue that there would have been no reasonable
expectation of success in combining the references. Dr. Saus opines, in
relevant part:
[0]ne of skill in the art would expect that cGPBP-specific
antibody treatment would not be effective to treat IC-GN, GPBP
causes basement membrane collagen misfolding, which is
expected to be accomplished inside the cell at the reticulum
endoplasmic [sic] where basement membrane collagen assembles
and antibodies cannot penetrate in this cellular compartment. The
’935 application discloses that increased cellular expression of
GPBP is associated with increased levels of cGPBP and therefore
extracellular cGPBP is a biomarker for monitoring what is
occurring inside the cell. However, one of skill in the art would
find it nonobvious and unexpected that blocking extracellular
cGPBP would have consequences on any deleterious effect of
intracellular GPBP such as its basement membrane collagen
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misfolding and IC-GN, since there is no known positive feedback
operating between extracellular (cGPHP) and intracellular
(GPBP).
Saus Deck 19 (emphases in original). We have considered the opinions of
Dr. Saus but are not persuaded they overcome the evidence of obviousness.
Rather, we agree with the Examiner that Revert 2007 and Revert 2008, both
of which list Dr. Saus as a coauthor, teach that the 77 kDa GBPB isoform is
also involved in the etiology of IC-GN beyond acting as a mere biomarker.
Revert 2008 teaches:
Here we show that cells expressed at least two GPBP isoforms
resulting from canonical (77-kDa) and noncanonical (91-kDa)
mRNA translation initiation. The 77-kDa polypeptide interacted
with type IV collagen and localized as a soluble form in the
extracellular compartment. The 91-kDa polypeptide and its
derived 120-kDa polypeptide associated with cellular
membranes and regulated the extracellular levels of the 77-kDa
polypeptide.
Revert 2008 Abstr. Revert 2008 also teaches: “Here we demonstrate that the
translation of the mRNA for GPBP generated several polypeptides, none of
which were significantly expressed in the cytosol. On the contrary, the
current study provides evidence that GPBP enters into the secretory
pathway and interacts with type IV collagen.'1'’ Revert 2008 30247 (emphasis
added). Revert 2008 also teaches:
Several lines of evidence support the idea that GPBP regulates
protein folding in the ER and supramolecular organization in the
extracellular compartment rather than interorganelle ceramide
traffic in the cytosol ...the 77-kDa GPBP is mainly found in the
extracellular compartment both soluble (Fig. 5) or associated
with glomerular basement membrane collagen (4) and is not
expressed at significant levels in the cytosol of cultured cells... an
increased expression of the 77-kDa GPBP perturbs the
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quaternary structure of type IV collagen, suggesting that the
elevated GPBP levels interfere with the conformational
diversification program (tertiary structure) of the a3(IV)NCl
domain.
Revert 2008 30254—55. Although these teachings do not contradict the
opinion of Dr. Saus that overexpression of GPBP within the cell, and
particularly the 99-kDa intracellular isoform, play an important role in
protein misfolding, the references also teach that the extracellular 77-kDa
isoform, i.e., cGPBP plays an external role in generating the autoimmune
response and GBM disruption characteristic of IC-GN. This latter isoform
would be understood by a person of ordinary skill to be predictably
susceptible to treatment with anti-cGPBP antibodies because since it has
been identified as interfering with the collagen structure, neutralizing it
would be reasonably expected to have at least some beneficial effect on the
disease.
Finally, Saus ’935 teaches:
Immunohistochemical evidence suggests that GPBP is primarily
extracellular, although with the potential to localize to various
intracellular sites (3,4). Protein distribution is highly informative
with respect to protein function; therefore additional studies were
needed to understand the biological function of GPBP. Here we
demonstrate that the translation of the mRNA for GPBP generated
several polypeptides, none of which were significantly expressed
in the cytosol. On the contrary, the current study provides
evidence that [the 77-kD isoform of] GPBP enters into the
secretory pathway and interacts with type IV collagen.
Saus ’935 1134 (emphasis added). The same reference teaches: “An
increased expression of the 77-kDa GPBP perturbs the quaternary structure
of type IV collagen, suggesting that the elevated GPBP levels interferes with
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the conformational diversification program (tertiary structure) of the
a3(IV)NCl domain .... Increased serum levels of GPBP correlates with type
IV-collagen based glomerulonephritis.” Saus ’935 1177. Moreover, we
have explained our reasoning with respect to paragraph [0071] of Saus ’935.
Taken together, we find that these teachings outweigh the opinion of
Dr. Saus that GPBP acts via an intracellular mechanism unavailable to
circulating antibodies. We consequently agree with the Examiner’s findings
and conclusion that a person of ordinary skill in the art would have a
reasonable expectation of success in combining the references to arrive at
Appellants’ claimed method.
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C. Unpredictability of the prior art
Issue
Appellants next argue that the Examiner erred because a person of
ordinary skill in the art would not have had a reasonable expectation of
success in arriving at Applicants’ claimed invention merely from the
combination of Bard with the other cited references at least because (1)
when considered in its totality, the art was unpredictable, and (2) Bard’s
teachings relate to an entirely different disease with an entirely different
pathology. App. Br. 12.
Analysis
Appellants argue that, at the time of filing, Bard was but one example
in the art of attempted treatment of a disease linked to overexpression of a
protein by administering an antibody specific for that protein. App. Br. 13.
Appellants point to another piece of prior art, S. Higa et al., Administration
of Anti-interleukin 18 Antibody Fails to Inhibit Development of Dermatitis in
Atopic Dermatitis-Model Mice NC/Nga, 149 British Journal of
Dermatology 39-45 (2003) (“Higa”). According to the Saus Declaration:
Higa, et al., teaches that increased IL-18 serum levels (e.g., a
circulating cytokine protein) were found to correlate with onset
and development of dermatitis [....] However, when the authors
investigated whether administration of anti-IL-18 antibody could
be used to treat dermatitis, they found that continuous injections
of anti-IL-18 antibody failed to inhibit the onset and
development of dermatitis. To the contrary, the treatment
tended to lead to an exacerbation of dermatitis and scratching
behavior.
Higa, et al., demonstrates that the effects on a disease of
administration of an antibody to a protein whose over-expression
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is associated with that disease cannot be reasonably predicted
by one of ordinary skill in the art.
App. Br. 13 (quoting Saus Decl. Tflf 13—14) (emphasis added by Appellants).
Appellants therefore argue that the Saus Declaration makes clear that to one
of skill in the art, the results of administration of an antibody to a protein, the
overexpression of which is correlated with a disease state, are unpredictable.
Id.
Appellants assert that the Examiner’s findings failed to consider the
teachings of Higa in their entirety. App. Br. 14. According to Appellants, at
the time of filing, both the rationale and the results of Higa were in the prior
art, and one of ordinary skill considering Higa as a whole, would have
understood that the art was unpredictable, and that there was no reasonable
expectation of success in treating a condition characterized by
overexpression of a protein using an antibody to that protein. Id.
Appellants argue further that, setting aside the teachings of Higa, even
the art within the field of Alzheimer’s disease, addressed by Bard, was and is
unpredictable. Appellants point to B. Spencer and E. Masliah,
Immunotherapy for Alzheimer’s disease: Past, Present and Future, 6(114)
Frontiers in Aging Neuroscience, 1-7 (2014) (“Spencer”). App. Br. 14.
Appellants assert Spencer reviews anti-Ap immunotherapies for the
treatment of Alzheimer’s disease, many of which failed. Id. Appellants
quote Spencer as teaching: “Although many of these immunotherapeutic
approaches have failed to affect significant improvements in the mild to
moderate AD patients being treated, the exact cause of failure is not known.”
Id. (quoting Spencer 4). Appellants contend that these failures, and the lack
of understanding regarding their causes, indicate confusion and
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unpredictability in the art—even within the same disease addressed by Bard.
Id. According to Appellants, the predictability and expectation of success is
even lower in applying the Alzheimer’s disease-based teachings of Bard to
IC-GN: an entirely different disease with a different pathology, using
different antibodies against a different protein target. Id. Appellants argue
that, in applying Bard to arrive at Appellants’ claimed methods of treating
IC-GN, one of skill would have had to make a number of substantial and
scientifically baseless assumptions regarding similarities between
Alzheimer’s disease and IC-GN. Id.
The Examiner responds that, in their arguments, Appellants do not
provide persuasive evidence that one skilled in the art would not have
accepted that the anti-Ap antibodies taught by Bard could be used to treat
Alzheimer’s. Ans. 21. Also, according to the Examiner, the issue shared in
the teachings of Bard, Revert 2007, and Revert 2008 is the overexpression of
a polypeptide with pathological features that can be treated with anti­
polypeptide antibodies, as long as the antibody is accessible to the
polypeptide. Id.
The Examiner finds that, in the instant application, studies involving
passive immunization have suggested that the primary mechanism for Ap
clearance is peripheral and is not due to antibodies entering the CNS. Id.
The Examiner finds that it has been shown that, following intraperitoneal
injection of anti-Ap antibodies in the PDAPP mouse, there is a rapid 1,000-
fold increase in circulating plasma Ap, suggesting that circulating ant-Ap
antibodies bind to plasma Ap and thus cause a disruption in the equilibrium
between the brain and plasma removing Ap from the brain. Id. (citing R.B.
DeMattos et al., Peripheral Anti-A/l Antibody Alters CNS and Plasma A ft
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Clearance and Decreases Brain Afi burden in a Mouse Model of Alzheimer’s
Disease, 98(15) Proc. Nat’l Acad. Sci. USA 8850-55 (2001).
The Examiner finds further that Higa supports the Examiner’s
position that those skilled in the contemporary art would have a reasonable
expectation of success that the antibody targeting of a protein whose
overexpression correlates with a specific disorder would be effective to treat
the disorder, because if there had been no such expectation, the study would
not have been attempted. Ans. 21.
We are not persuaded by Appellants’ arguments. As an initial matter,
the Spencer reference was published in 2014 and is therefore does not reflect
evidence the state of the art at the time of invention. The obviousness
analysis, rather, is determined by what the combined teachings of the prior
art references would have suggested [at the time of Appellants’ claimed
invention] to those of ordinary skill in the art. In re Keller, 642 F.2d 413,
425 (CCPA. 1981). We therefore do not reach Appellants’ arguments with
respect to the teachings of Spencer.
Although we acknowledge that Higa teaches a different outcome from
that of Bard, only a reasonable expectation of success, not absolute
predictability, is necessary for a conclusion of obviousness. See In re Longi,
795 F.2d 887, 897 (Fed. Cir. 1985). Inasmuch as Higa teaches that
“[sjurprisingly” the administration of its antibodies did not inhibit the
disorder, Higa evidences that skilled persons would have reasonably
expected the opposite result. (Higa 41.) We agree with the Examiner that
the teachings of Bard would provide a reasonable basis for a person of
ordinary skill in the art to expect success in attempting to apply the method,
as suggested by Saus ’935, of directing antibodies against the circulating 77-
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kDa isoform of GPBP as a means of treating IC-GN. We consequently
affirm the Examiner’s rejection of the claims.
DECISION
The Examiner’s rejection of claims 4—5 and 20—30 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)(1).
AFFIRMED
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