Ex Parte Al-Abed

Patent Trial and Appeal Board

Feb 1, 2017

10594641 (P.T.A.B. Feb. 1, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/594,641 03/28/2008 Yousef Al-Abed 50425/262 1663
1912 7590 02/03/2017
AMSTER, ROTHSTEIN & EBENSTEIN LLP
90 PARK AVENUE
NEW YORK, NY 10016
EXAMINER
EWOLDT, GERALD R
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
02/03/2017 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte YOUSEF AL-ABED1
Appeal 2015-008264
Application 10/594,641
Technology Center 1600
Before MELANIE L. McCOLLUM, TAWEN CHANG, and DEVON
ZASTROW NEWMAN, Administrative Patent Judges.
McCOLLUM, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134 involving claims to a method
for inhibiting the development of type 1 diabetes. The Examiner has
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 Appellant identifies the real party in interest as The Feinstein Institute for
Medical Research (App. Br. 3).
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Application 10/594,641
STATEMENT OF THE CASE
Claims 29-33 are on appeal (App. Br. 3).2 The claims subject to each
rejection have not been argued separately and therefore stand or fall
together. 37 C.F.R. § 41.37(c)(l)(iv). Claims 29 and 33 are representative
and read as follows:
29. A method of inhibiting the development of type 1 diabetes in a
mammal at risk for type 1 diabetes, the method comprising administering to
the mammal a pharmaceutical composition comprising an amount of an
agent effective to inhibit the development of type 1 diabetes in a mammal at
risk for type 1 diabetes, wherein the agent comprises a binding site of an
antibody that binds specifically to macrophage migration inhibitory factor
(MIF).
33. The method of claim 29, wherein the antibody is a humanized
antibody.
Claims 29-32 stand rejected under 35 U.S.C. § 103(a) as obvious over
Bojunga3 in view of Nishihira4 and Shoelson5 (Ans. 2).
Claim 33 stands rejected under 35 U.S.C. § 103(a) as obvious over
Bojunga in view of Nishihira, Shoelson, and Queen6 (Ans. 4).
2 Claims 36 and 37 are also pending but have been withdrawn from
consideration (App. Br. 3).
3 Jorg Bojunga et al., Macrophage Migration Inhibitory Factor and
Development of Type-1 Diabetes in Non-Obese Diabetic Mice, 21 Cytokine
179-86 (2003).
4 Jun Nishihira & Akihiko Ogata, Macrophage Migration Inhibitory Factor
as a Target Molecule in Multiple Sclerosis, 2 Current Opinion
Investigational Drugs 778—82 (2001).
5 Shoelson, US 6,468,755 Bl, Oct. 22, 2002.
6 Queen et al., US 5,530,101, June 25, 1996.
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Claims 29-32 stand rejected under 35 U.S.C. § 103(a) as obvious over
Al-Abed7 in view of Nishihira and Shoelson (Ans. 4).
Claim 33 stands rejected under 35 U.S.C. § 103(a) as obvious over
Al-Abed in view of Nishihira, Shoelson, and Queen (Ans. 5).
I
In rejecting representative claim 29, the Examiner relies on Bojunga
for teaching “the treatment of diabetes comprising the administration of a
MIF inhibitor” (Ans. 2). The Examiner finds: “Figure 3 of the reference
further teaches that increased MTF-RNA expression precedes that onset of
disease. Figure 4 of the reference teaches that from the time of MIF
administration 4-10 weeks is required before the onset of disease.” (Id.)
The Examiner relies on Nishihira for teaching “the treatment of
autoimmune diseases with an anti-MIF antibody and a small organic
molecule and that the treatments are essentially . . . interchangeable” (id.).
The Examiner finds that the “reference further teaches that MIF is essential
for T cell activation” (id.).
The Examiner relies on Shoelson for teaching “the interchangeability
of an antibody and a small molecule in the context of inhibiting a specific
protein activity for the treatment of type-1 diabetes” (id. at 3).
The Examiner concludes:
It would have been prima facie obvious to one of ordinary skill
in the art at the time the invention was made to treat diabetes, as
taught by Bojunga et al., with an anti-MIF antibody because
Nishihira . . . teach[es] that small organic molecules are
interchangeable with antibodies in the context of the treatment of
7 Al-Abed et al., WO 01/32606 Al, May 10, 2001.
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Application 10/594,641
autoimmune disease, and, in view of [Shoelson], particularly in
the context of inhibiting a specific protein activity for the
treatment of type-1 diabetes. . . . Additionally, it would be
obvious to treat a patient at risk of developing disease given the
teachings of Bojunga et al. that, a) increased MIF-RNA
expression precedes that onset of disease, and b) MIF
administration precedes the onset of disease in the experiments
of the reference, and c) Nishihira . . . teach[es] that MIF is
essential for T cell activation. Clearly T cell activation precedes
disease onset (given that T cells are disease effectors) thus, it
would be obvious to block the disease-causing effects of MIF as
well as T cell activation before the onset of disease.
(Id.)
With regard to claim 33, the Examiner additionally relies on Queen
for teaching humanized antibodies (id. at 4).
Analysis
Upon review of the Final Rejection and Examiner’s Answer, we
conclude that the Examiner has set forth a prima facie case, which is
summarized above, that claim 29 would have been obvious over Bojunga,
Nishihira, and Shoelson and that claim 33 would have been obvious over
Bojunga, Nishihira, Shoelson, and Queen. Appellant argues, however, that
“the art as a whole shows there was ... no reasonable expectation of success
of the claimed method at the time of filing” (App. Br. 4). We are not
persuaded.
Bojunga investigates “the potential role of MIF in the development of
autoimmune-mediated diabetes mellitus” (Bojunga 179). Bojunga discloses:
MTF-mRNA expression was markedly increased in splenic
lymphocytes of spontaneously diabetic NOD [non-obese
diabetic] mice as well as in 8-week-old NOD mice treated with
cyclophosphamide[, which accelerates spontaneous diabetes,]
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compared with 2-week-old non-diabetic NOD and healthy . . .
control mice. Western blot analyses showed decreased
lymphocytic MIF-protein content in diabetic as well as in
cyclophosphamide-treated animals compared with 2-week-old
non-diabetic NOD and healthy . . . mice, probably as a
consequence of increased protein secretion. Furthermore,
treatment of NOD mice with recombinant MIF-protein at 25 jig
twice a week, from age 6 to 11 weeks, led to an increased
diabetes incidence (86%; n = 7) compared with untreated control
groups (55%; n = 20) at week 34.
{Id. at 179-180.) Bojunga concludes that their data “suggests that anti-MIF
therapeutic strategies might serve to attenuate various autoimmune processes
like type-1 diabetes” {id. at 185).
We understand Appellant’s position that “Bojunga did not
demonstrate that the elevation of MIF mRNA expression was associated
with an elevated level of endogenous MIF protein” and that “the claimed
treatment comprises an anti-MIF protein antibody binding site, not an anti-
mRNA agent” (App. Br. 6). We also acknowledge Appellant’s position,
which relies on Lutz8 and Cusi,9 10that the “diabetes art does not show any
predictable correlation between mRNA levels and protein levels, and in the
specific case of MIF, Ogata[10] and Bojunga do not show a predictable
correlation” and that, therefore, there “is no reasonable predictability that
8 AJ Lutz & WM Pardidge, Insulin Therapy Normalizes GLUT1 Glucose
Transporter mRNA but not Immunoreactive Transporter Protein in
Streptozocin-Diabetic Rats, 42 Metabolism 939-44 (1993) (Abstract only).
9 KJ Cusi et al., Exercise Increases Hexokinase II mRNA, but not Activity in
Obesity and Type 2 Diabetes, 50 Metabolism 602—06 (2001) (Abstract only).
10 Akihiko Ogata et al., Identification of Macrophage Migration Inhibitory
Factor mRNA Expression in Neural Cells of the Rat Brain by in situ
Hybridization, 246 Neuroscience Letters 173—77 (1998).
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simply because elevated MIF mRNA was observed, elevated MIF protein
was present, especially when no elevated MIF protein was measured” (id. at
7). In addition, we acknowledge Appellant’s argument, relying on
D’Hertog,11 that it was “known, specifically in diabetes research, that
mRNA offers little or no guidance as to therapeutic targets” (id. ).
However, as pointed out by the Examiner (Ans. 8; see also Ans. 2,
referencing Bojunga Fig. 4), in addition to the mRNA data, Bojunga
discloses that they “tested the effect of MIF-protein treatment on diabetes
incidence in [their] NOD mice colony” and that “MIF treatment at
25 jig/mouse twice a week from age 6 to 11 weeks—the ‘vulnerable phase’
of diabetes development. . . —led to an increase in diabetes incidence to
86% (6/7) compared with untreated NOD mice, which became diabetic in
55% (11/20)” (Bojunga 184). As noted by Appellant (App. Br. 9), Bojunga
states that “this trend was statistically not significant (p = 0.07)” (Bojunga
184). Nevertheless, we conclude that Appellant has not adequately
countered the Examiner’s position that this is data that one of ordinary skill
in the art would have reasonably relied upon to select MIF as a target
(Ans. 8-9).
In addition, we recognize that Bojunga states that their data “suggests
that anti-MIF therapeutic strategies might serve to attenuate various
autoimmune processes like type-1 diabetes” (Bojunga 185 (emphasis
11 Wannes D’Hertog et al., Type 1 Diabetes: Entering the Proteomic Era,
3 Expert. Rev. Proteomics 223—36 (2006). We note that this reference is not
prior art and therefore may not reflect what was known in the art at the time
of the invention.
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added)). However, we do not agree with Appellant that use of the term
“might” is sufficient to demonstrate that there would not have been a
reasonable expectation for success.
We also understand, as taught by Lan,12 that “[gjenes whose
expression levels change in a disease state may or may not be related to the
etiology or pathology of the underlying disease” (Lan 240). In addition, we
acknowledge that Lan discloses that “[t]his was particularly evident in
diabetes research” (id.). However, as discussed above, we conclude that the
MIF treatment data supports the Examiner’s position that there would have
been a reasonable expectation for success.
With regard to Nishihira, Appellant argues:
[I]t is stated in the “Perspectives” section that “the therapeutic
use of anti-MIF antibodies and small molecules inhibiting MIF
activity could be promising for septic shock...” There is no
statement of general interchangeability here. Moreover, there is
no broad extrapolation that inhibiting MIF can treat
“autoimmune diseases” in general and also diabetes.
(App. Br. 10.) Furthermore, Appellant argues that, “while [Shoelson] is
cited for the notion of ‘interchangeability of an antibody and a small organic
molecule in the context of inhibiting’ a protein known as IKK-Beta for the
treatment of type-1 diabetes, IKK-Beta is not MIF” (id.). We are not
persuaded.
Nishihira and Shoelson are relied upon by the Examiner to
demonstrate that it would have been obvious to use anti-MIF antibodies, as
12 Hong Lan et al., Distinguishing Covariation From Causation in Diabetes
A Lesson From the Protein Disulfide Isomerase mRNA Abundance Trait, 53
Diabetes 240-44 (2004).
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well as small molecules, in the anti-MIF therapeutic strategies of Bojunga
(Ans. 2—3). We understand that Nishihira does not teach diabetes and that
Shoelson does not teach MIF. However, Appellant’s arguments do not
persuade us that Nishihira and Shoelson do not suggest using anti-MIF
antibodies in Bojunga’s anti-MIF therapeutic strategies. In addition, as
noted by the Examiner (Ans. 9), Nishihira does conclude that “it is expected
that. . . anti-MIF therapy could be used for various immune-mediated
diseases, including MS” (Nishihira 781 (emphasis added)), suggesting
broader applicability that just the diseases mentioned in Nishihira.
In addition, Appellant argues that it was “known in the diabetes
literature, on a more overarching level, that trying to predict the success of a
potential treatment based on a mechanistic theory, rather than empirical
animal model results, has been difficult” (App. Br. 10). In support of this
position, Appellant refers to Fraenkel,13 Sparre,14 and Jiang15 (id.). In view
of this evidence, Appellant argues that, “absent applicant’s work disclosed in
the specification, there was no reasonable expectation nor predictability that
13 Merav Fraenkel et al., mTOR Inhibition by Rapamycin Prevents fi-Cell
Adaption to Hyperglycemia and Exacerbates the Metabolic State in Type 2
Diabetes, 57 Diabetes 945—57 (2008). We note that this reference is not
prior art and therefore may not reflect what was known in the art at the time
of the invention.
14 Thomas Sparre et al., Unraveling the Pathogenesis of Type 1 Diabetes
with Proteomics, 4 Molecular & Cellular Proteomics 441—57 (2005).
15 Yong-Liang Jiang et al., Alteration of the Proteome Profile of the
Pancreas in Diabetic Rats Induced by Streptozotocin, 28 Inf 1 J. Molecular
Medicine 153—60 (2011). We note that this reference is not prior art and
therefore may not reflect what was known in the art at the time of the
invention.
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simply administering an anti-MIF antibody could inhibit the development of
T1D [type 1 diabetes] in a subject” (id. at 11). Instead, Appellant argues that
“it is clear the skilled artisan could not have a reasonable expectation that a
potential therapeutic agent directed against a target identified by a
mechanistic theory could be successfully used to treat diabetes until the
therapeutic agent was proven efficacious in an animal model” (id. ). We are
not persuaded.
Fraenkel shows that hypotheses regarding potential therapeutic agents
are not always correct (Fraenkel, Abstract). However, we do not find this
evidence sufficient to demonstrate that, in the present case, there could be no
reasonable expectation of success “until the therapeutic agent was proven
efficacious in an animal model” (App. Br. 11).
Sparre, the only one of the three references cited in this argument that
could be prior art and therefore more likely to reflect what was known in the
art at the time of the invention,16 discloses: “[I]t is beyond any doubt that
T1D is a multifactorial polygenic disease of largely unknown etiology. . . .
[SJeveral proteins seem to be involved in the pathogenesis of diabetes and
. . . no single protein can be accused of being ‘The Diabetes Protein.’”
(Sparre 452.) However, we do not agree that Appellant has shown that
Sparre, or Jiang, demonstrates that the teachings of Bojunga “that anti-MIF
therapeutic strategies might serve to attenuate various autoimmune processes
like type-1 diabetes” (Bojunga 185) would not have been believed.
16 Sparre appears to indicate that it was published on February 7, 2005,
which is before the PCT filing date of the present application, but after the
claimed benefit date.
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Conclusion
The evidence supports the Examiner’s conclusion that Bojunga,
Nishihira, and Shoelson suggest the method of claim 29. We therefore
affirm the obviousness rejection of claim 29 over these references.
Claims 30—32 fall with claim 29.
The evidence also supports the Examiner’s conclusion that Bojunga,
Nishihira, Shoelson, and Queen suggest the method of claim 33. We
therefore affirm the obviousness rejection of claim 33 over these references.
II
In a second set of rejections, the Examiner relies on Al-Abed for
teaching “the treatment or prevention of type 1 (insulin dependent) diabetes
comprising the administration of a MIF inhibitor” (Ans. 4). The Examiner
relies on Nishihira and Shoelson as discussed above {id. at 5). The
Examiner concludes:
It would have been prima facie obvious to one of ordinary skill
in the art at the time the invention was made to treat or prevent
diabetes, as taught by [Al-Abed], with an anti-MIF antibody
because Nishihira . . . teach[es] that small organic molecules are
interchangeable with antibodies in the context of the treatment of
autoimmune disease and, in view of [Shoelson], particularly in
the context of inhibiting a specific protein activity for the
treatment of type-1 diabetes.
{Id.)
With regard to claim 33, the Examiner additionally relies on Queen
for teaching humanized antibodies (id. at 5—6).
Analysis
Upon review of the Final Rejection and Examiner’s Answer, we
conclude that the Examiner has set forth a prima facie case, which is
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summarized above, that claim 29 would have been obvious over Al-Abed,
Nishihira, and Shoelson and that claim 33 would have been obvious over
Al-Abed, Nishihira, Shoelson, and Queen.
Appellant argues, however, that Al-Abed “in the combination of cited
art does not change the conclusion from the prior art as a whole that there
would be no reasonable predictability and no reasonable expectation of
success of the claimed method ... at the time of filing” (App. Br. 13). We
are not persuaded for the reasons discussed above.
Conclusion
The evidence supports the Examiner’s conclusion that Al-Abed,
Nishihira, and Shoelson suggest the method of claim 29. We therefore
affirm the obviousness rejection of claim 29 over these references.
Claims 30—32 fall with claim 29.
The evidence also supports the Examiner’s conclusion that Al-Abed,
Nishihira, Shoelson, and Queen suggest the method of claim 33. We
therefore affirm the obviousness rejection of claim 33 over these references.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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