Ex Parte Isaacs et al

Patent Trial and Appeal Board

Jun 28, 2016

10491112 (P.T.A.B. Jun. 28, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
10/491,112 10/01/2004 John Isaacs
27162 7590 06/29/2016
CARELLA, BYRNE, CECCHI, OLSTEIN, BRODY & AGNELLO
5 BECKER FARM ROAD
ROSELAND, NJ 07068
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.
695458-114 6163
EXAMINER
SKELDING, ZACHARY S
ART UNIT PAPER NUMBER
1644
MAILDATE DELIVERY MODE
06/29/2016 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 JOHN ISAACS, HERMAN WALDMANN, and
GEOFFREY HALE 1
Appeal2013-009136
Application 10/491, 112
Technology Center 1600
Before ERIC B. GRIMES, ULRIKE W. JENKS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims directed to a
method of treating chronic joint inflammation due to rheumatoid arthritis by
administering an anti-CD3 antibody having a mutated Fe region. The
Examiner rejects the claims as anticipated and obvious. We have
jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
1 According to Appellants, the Real Party in Interest is Glaxo Group
Limited. (Br. 1.)
Appeal2013-009136
Application 10/491,112
STATEMENT OF THE CASE
Claims 14--21, 27-30, 32, 33, 35-37, 40-44, 46-48, and 50-52 are on
appeal, 2 and can be found in the Claims Appendix of the Appeal Brief.
Claim 51 is representative of the claims on appeal, and reads as follows:
51. A method of treating chronic joint inflammation in a
human patient having rheumatoid arthritis comprising
administering to a human patient in need of said treating a
therapeutically effective dose of an anti-CD3 antibody, wherein
said antibody is mutated in the F c region to reduce binding to
Fe receptors.
(Br. 27 (Claims Appendix.)
The following grounds of rejection are before us for review:
I. claims 28-30, 32, 33, 35-37, 40-44, 46-48, and 51under35 U.S.C.
§ 103(a) as unpatentable over Bach3 in view of Smith, 4 Hughes, 5
Malfait6 ·
'
II. claims 14--21, 27, 50, and 52 under 35 U.S.C. § 103(a) as
unpatentable over Bach in view of Smith, Hughes, 1\1alfait, and
further in view ofWaldmann7; and
2 Claim 25 is withdrawn as being directed to a non-elected species (see Final
Act. 2; Ans. 3).
3 Bach et al., CA 2,224,256, published June 9. 1999 ("Bach")
4 Smith et al., WO 98/47531, published Oct. 29, 1998 ("Smith").
5 Hughes et al., Induction of T Helper Cell Hyporesponsivness in an
Experimental Model of Autoimmunity by Using Nonmitogenic Anti-CD3
Monoclonal Antibody, 153 J. IMMUN. 3319-3325 (1994) ("Hughes").
6 Malfait et al., Chronic Relapsing Homologous Collagen-Induced Arthritis
in DBN/l Mice as a Model for Testing Disease-Modifying and Remission-
Inducing Therapies, 44 ARTH. &RHEUM. 1215-1224 (2001) ("Malfait").
7 Waldmann et al., WO 00/05268, published Feb. 3, 2000 ("Waldmann").
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III. claims 40-44, 46, 47, and 51under35 U.S.C. § 102(b) as being
anticipated by Tso 8 as evidenced by Kraan. 9
I. & II. Obviousness over Bach, Smith, Hughes, and Malfait
There are two obviousness rejections, but both rely on the combined
teachings of Bach, Smith, Hughes, and Malfait, so we will discuss them
together. Because the claims are not separately argued, we focus our
discussion on representative claim 51.
The issue is: Does the preponderance of evidence of record support
the Examiner's conclusion that using anti-CD3 antibodies having a mutated
Fe region in human patients with rheumatoid arthritis (RA) would have a
reasonable expectation of treating patients having chronic joint
inflammation?
Findings of Fact
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art (see Final Act. 3-9 10; Office Act. 5-21 11 ;
Ans. 4--42). For emphasis only we highlight the following:
FF 1. Bach teaches "[a] method of treating spontaneous and ongoing
autoimmune diseases in mammals, comprising administering to a
mammal, in need of such a treatment, a therapeutically effective
amount of one or more non mitogenic anti-CD3 active principles to
achieve permanent disease remission through the induction of antigen-
8 Tso et al., US 5,834,597, issued Nov. 10, 1998 ("Tso").
9 Kraan et al., Asymptomatic Synovitis Precedes Clinically Manifest
Arthritis, 41 Arth. & Rheum. 1481-1488 (1998) ("Kraan").
1° Final Office Action, mailed Feb. 16, 2012 ("Final Act.").
11 Office Action, mailed July 14, 2011 ("Office Act.").
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Application 10/491,112
specific unresponsiveness, i.e. immune tolerance" (Bach 11, 12 claim 1,
see Abstract; Office Act. 5). Autoimmune diseases treated with the
antibody include rheumatoid arthritis (Bach 12, claim 1 O; Office
Act. 5). The antibody dosage is 5 to 20 mg (Bach 14, claim 29; Office
Act. 6)
FF2. The Examiner finds that Bach does not "teach the use of an anti-CD3
antibody that has been a mutated in the Fe region" (Office Act. 6).
FF3. The Examiner finds that "Smith teaches anti-CD3 antibodies mutated
in the Fe region to reduce Fe [receptor] binding" (Office Act. 6; see
Smith 88 ("a 'humanized' mAb derived from OKT3 and bearing
mutations of 2 amino acids in the Fe portion to impede its binding to
FcTRs does not induce human T cell activation in vivo in a preclinical
model, but retains the immunosuppressive properties of the native
mAb")).
FF4. Hughes teaches that treatment with "nmCD3 [(anti-CD3 mAb )]
delayed the onset and reduced the severity of arthritis in mice
immunized with type II collagen (CII)" (Hughes, Abstract; Office
Act. 6). "F(ab')2 fragments of 145-2Cl 1 were prepared by incubating
purified mAb with pepsin" (Hughes, 3320).
FF5. Hughes teaches that "[t]he first dose of mAb or PBS was administered
at the same time as the first CII immunization" (Hughes, 3320).
FF6. Malfait teaches that "[t]he chronic relapsing form of CIA [collagen-
induced arthritis] more closely resembles RA" (Malfait 1221).
12 The claims section of Bach lacks page numbers but the descriptive section
ends on page 10. We therefore consider the first page of claims to be page
11, and number the remaining pages consecutively.
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"Chronic relapsing CIA starts as a milder disease than classic CIA"
(id.). Malfait suggests that "the chronic model could be used after
initial screening of a candidate treatment in classic CIA in order to
confirm the therapeutic effect in a chronic relapsing arthritis" (id. at
1223.)
FF7. Malfait shows that "[t]wo injections of ... [anti-CD3 plus anti-TNF]
antibodies at disease onset suppressed the arthritis for the entire
duration of the experiment" (Malfait 1221; Office Act. 6). The anti-
CD3 antibody used in the experiment is "145-2C 11 hamster IgG 1"
(Malfait 1216, therapeutic agents).
FF8. The Specification discloses that "[t]he dose of antibody to be
administered to a patient will depend on the condition of the patient
and will be at the discretion of the attendant physician." (Spec. 13:
12-14; see Final Act. 3; Office Act. 7.)
FF9. Kraan "hypothesized that asymptomatic synovitis may precede the
clinical manifestations of RA [rheumatoid arthritis] and that so-called
early RA is already a chronic disease. This is supported by the
observation that a notable percentage of RA patients have signs of
joint destruction at the time of initial diagnosis" (Kraan 1481 ). Kraan
used a monkey model to study synovial biopsy during the progression
of the disease. "The results clearly indicate that synovial
inflammation is present before the joints become painful and swollen"
(Kraan 1487). Thus, "when the patient gets signs and symptoms of
RA, infiltration with inflammatory cells that may induce joint
destruction have been present in the joints for a while" (Kraan 1488).
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FFIO. Kraan teaches that "[i]t is obvious that prevention of disability in RA
patients may be more successful when down-modulation of the
process underlying joint destruction is achieved in early phases rather
than in later phases of the disease" (Kraan 1488).
Principle of Law
"Obviousness does not require absolute predictability of success." In
re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988); see also Hoffmann-La
Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014)
("Conclusive proof of efficacy is not necessary to show obviousness."). The
expectation of success need only be reasonable. Pfizer, Inc. v. Apotex, Inc.,
480 F.3d 1348, 1364 (Fed. Cir. 2007)
([A] rule of law equating unpredictability to patentability ...
would mean that any new salt-including those specifically
listed in the [prior art patent] itself-would be separately
patentable, simply because the formation and properties of each
salt must be verified through testing. This cannot be the proper
standard since the expectation of success need only be
reasonable, not absolute.).
Analysis
We adopt the Examiner's findings and conclusion and agree with the
Examiner's responses to Appellants' contentions (see Final Act. 3-9; Office
Act. 5-21; Ans. 4--42; see FF1-FF7). To summarize, Bach tells one of
ordinary skill in the art to treat autoimmune disease, such as rheumatoid
arthritis, with anti-CD3 monoclonal antibodies and fragments thereof (FFl ).
The Examiner acknowledged that Bach does not disclose antibodies with
mutated Fe regions (FF2) and relies on the other three references to support
the use of such antibodies (FF3-FF7). The Examiner concludes that it
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would have been obvious to one of ordinary skill in the art "to employ the
non-mitogenic anti-CD3 antibodies of Smith to treat rheumatoid arthritis
since these antibodies lack the toxicity of mitogenic anti-CD3 antibodies and
yet retain the potential for 'Th2 cytokine deviation' and therefore for
'suppressing Thi-mediated autoimmune diseases,' as taught by Smith"
(Final Act. 6-7). We agree with the Examiner's reasoning and conclusion
and find that the combination of Bach, Smith, Hughes, and Malfait cited by
the Examiner provides a reasonable expectation of treating chronic joint
inflammation associated with rheumatoid arthritis by administering an anti-
CD3 antibody having a mutated Fe region as claimed. We address
Appellants' arguments below.
Appellants contend that "[ t ]he present invention differs from the prior
art in that the present invention is defined as treatment of 'chronic joint
inflammation in a human patient having rheumatoid arthritis.' This chronic
phase of rheumatoid arthritis occurs later in the disease progression after the
acute inflammation processes ... have failed to resolve." (Br. 4--5); and that
animal models do not provide predictive correlation of success in treating
chronic joint inflammation of rheumatoid arthritis with T-cell antibodies in
humans (id. at 4--20; see id. at 6 ("animal models of chronic human diseases
are especially imperfect")). Specifically, according to Appellants, because
the "exact role of T-cells and specific T-cell subsets in early and in
established disease remains unclear, [and] their important interactions with
other cell subsets have [not] been sufficiently clarified to predict clinical
responses on the basis of cell type or cell surface antigen targeted, and
"animal models of rheumatoid arthritis were shown not to be predictive of
success with respect to anti-CD4, anti-CDS, anti-CD7, and CAMPATH-1
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(anti-CD52) antibodies in clinical trials" (Br. 11, citing the Strand
Declaration 13), the animal models of Hughes and Malfait, "which teach the
treatment of arthritis at or before the onset [of chronic joint inflammation]
with an anti-CD3 antibody[,] do not create a reasonable expectation of
treating successfully chronic joint inflammation in a human rheumatoid
arthritis patient" (id. at 13). We are not persuaded.
Appellants' argument is grounded in the position that "treating
chronic joint inflammation in a human patient having rheumatoid arthritis,"
as required by claim 51, is fundamentally different than the prior art teaching
of treating rheumatoid arthritis. We find the prior art supports the
Examiner's position to the contrary. The Examiner cites Kraan as evidence
that by the time one is identified as having rheumatoid arthritis, the disease
in the joint of that patient is already considered chronic, and, thus, one
cannot distinguish "'treating chronic joint inflammation in a human patient
having rheumatoid arthritis' from the obviousness of treating [a patient
identified as having] rheumatoid arthritis" (Ans. 7; see FF9 & FFlO). As
explained by the Examiner, "even before a patient steps into a clinic
reporting the presence of painful and swollen joints for the first time, i.e.,
even prior to the outward symptoms of clinically manifest joint
inflammation, the joints of rheumatoid arthritis patients are already subject
to chronic inflammation." (Ans. 7 .) We find Kraan supports the Examiner's
interpretation that a patient with rheumatoid arthritis is a patient that already
has chronic inflammation (Kraan 1481-1482, 1487-88; FF9 and FFlO), and,
thus, the teaching in the prior art of treating inflammation in a patient
13 Declaration by Dr. Vibeke Strand signed Oct. 8, 2009, submitted on
Information Disclosure Statement May 6, 2010 ("Strand Dec.").
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Application 10/491,112
identified as having rheumatoid arthritis with anti-CD3 antibodies, i.e.,
Bach, Hughes, and Malfait, necessarily involves treating chronic joint
inflammation.
We also disagree with Appellants position that Hughes and Malfait
cited by the Examiner do not provide a reasonable expectation of treating
chronic joint inflammation associated with rheumatoid arthritis. First,
animal testing remains generally recognized as a valuable tool in the
screening for agents for the application to human diseases, even for treating
human patients identified as having rheumatoid arthritis, and thus, chronic
joint inflammation. It is important to point out that animal models,
generally, sort therapies into two groups: those that have the potential to
work and those that do not work. Although successful treatments in animal
models may not be absolutely predictive of success when applied to humans,
these models remain "useful for identification of therapeutic agents for RA"
(Ans. 12 (citing the Williams Declaration 14)). On the other hand, a negative
result in an animal model usually evinces a reason not to pursue application
of that substance in the modeled disease state.
Malfait teaches two types of animal models the chronic relapsing CIA
and the more traditional collagen induced model (FF6 and FF7). Malfait
suggests using the chronic relapsing CIA model after the initial screening
with the traditional model (FF6). The Examiner explains:
[ t ]he teachings of Malfait that are of primary relevance to the
prima facie case of obviousness ... are that in the homologous
collagen induced arthritis animal model[, the chronic relapsing
14 Declaration by Dr. Richard Williams, submitted on Information
Disclosure Statement Oct. 1, 2010 ("Williams Dec.").
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CIA ofMalfait,] ... administration of two doses of anti-CD3
and anti-TNFa antibodies at the onset of outward symptoms of
clinically manifest joint inflammation (days 28 and 32),
induced complete remission for the duration of the experiment.
(Ans. 14; see FF7.) "[T]he collagen induced arthritis mouse model was (and
is) a widely used, art accepted protocol for determining if a given therapeutic
agent would be reasonably expected to successfully treat a human patient"
(Ans. 12). The Examiner explains that the failure of using depleting
antibodies, e.g., anti-CD4, anti-CDS, anti-CD7, and CAMPATH-1
antibodies, does not negate the teachings in the art with respect to the non-
depleting anti-CD3 antibodies because the mechanism of action differs
between the two types of antibodies (see Ans. 26, 28, 41). We agree with
the Examiner's conclusion that the success shown using anti-CD3 antibodies
in the art in "treating rheumatoid arthritis in a collagen induced arthritis
mouse model prior to, or just after disease onset, ... recognizes that such an
antibody will be reasonably expected to successfully treat a human
rheumatoid arthritis patient" as well (Ans. 16). Importantly, a finding of
"[ o ]bviousness does not require absolute predictability of success." In re
O'Farrell, 8S3 F.2d at 903.
As further explained by the Examiner the failure in treating
rheumatoid arthritis with anti-CD4 and -CDS antibodies is due to "a variety
of technical reasons, [for example that] the patients did not receive
sufficiently high doses of depleting antibody to substantively affect the
pathogenic T cells in their synovial tissue" (Ans. 27 (emphasis removed)).
"[T]he primary publications describing these clinical 'failures' do not teach
or suggest depleting anti-CD4, -CDS or ---CDwS2 antibodies failed to
demonstrate therapeutic efficacy because CD4+ or CDS+ or CDwS2+ T
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cells are unimportant in disease pathology" (Ans. 27 (emphasis removed)).
Thus, T-cells remain important targets in the disease pathology. As
explained by the Examiner "it is significant that non-depleting anti-CD4
antibodies exert their effects via immunomodulatory-type mechanisms, such
as CD4 downmodulation" (Ans. 27). This is the same mechanism of action
as that of anti-CD3 antibodies (id.). We agree with the Examiner's
conclusion that "the knowledge of one of ordinary skill in the art pertaining
to the use of anti-T cell antibodies to treat rheumatoid arthritis would not
have negated the reasonable expectation of success that one of ordinary skill
would have had for treating rheumatoid arthritis with an anti-CD3 antibody
in view of the prior art teachings of Bach, Smith, Hughes and Malfait" (Ans.
28).
Additionally, Appellants contend that "Kraan teaches away from the
present invention by stating that rheumatoid arthritis needs to be treated
before it has become chronic" (Br. 8).
We are also not persuaded by Appellants contention with respect to
the teachings of Kraan. Although we recognize that Kraan suggests the
desirability to target treatment early in the disease process underlying joint
destruction to prevent disability (FF 10), a recognition that prevention of
disability is desirable does not mean that prevention of disability has to
occur before development of chronic inflammation. (FF9; see Ans. 13).
Kraan explains that "when the patient gets signs and symptoms of RA,
infiltration with inflammatory cells that may induce joint destruction have
been present in the joints for a while" (FF9 and FFlO). We agree with the
Examiner that teaching the desire to identify a patient early in the disease
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process, even before symptoms arise (see Ans. 12-13), does not teach away
from treating rheumatoid arthritis after the presentation of disease.
On the record before us, we conclude the Examiner did not err in
rejecting claim 51under35 U.S.C. § 103(a) as being unpatentable over the
combination of Bach, Smith, Hughes, and Malfait. Claims 28-30, 32, 33,
35-37, 40-44, and 46-48 were not separately argued and fall with claim 51.
Appellants have waived arguments directed to Waldmann (see Br. 22), and
therefore we also affirm the rejection of claims 14--21, 27, 50, and 52 under
35 U.S.C. § 103(a) as unpatentable over Bach in view of Smith, Hughes,
Malfait, and further in view of Waldmann.
III. Anticipation by Tso
The issue is: Does the preponderance of the evidence of record
support the Examiner's conclusion that treating patients having symptoms of
rheumatoid arthritis with an anti-CD3 antibody having Fe region mutation
necessarily treats a chronic inflammation as claimed?
Findings of Fact
FFl 1. Tso teaches antibodies having
mutated IgG2 constant regions comprising a nonnaturally
occurring segment of amino acids between residues 234 and
237 defined by the EU numbering system. Anti-CD3
antibodies incorporating such IgG2 constant regions can
specifically bind to CD3 antigens on T-cells without inducing a
mitogenic response in the T-cells through specific binding to
Fey receptors.
The immunoglobulin specifically binds to a CD3 antigen on the
surface of T cells and usually has a binding affinity having a
lower limit of about 107 M-1 and an upper limit of about five-
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times the binding affinity of the M291 immunoglobulin.
(Tso 2: 15-21.)
FF12. Tso teaches
Pharmaceutical compositions comprising [the anti-CD3]
antibodies ... are useful for parenteral administration ... [for]
conditions manifesting undesired immune responses ... .
Exemplary autoimmune diseases are rheumatoid arthritis,
multiple sclerosis, type I diabetes, system[ic] lupus
erythematosus and inflammatory bowel disease.
(Tso 11: 56-67 (emphasis added).)
FF13. Tso teaches that the anti-CD3 "antibodies can be administered for
prophylactic and/or therapeutic treatments .... Amounts effective for
this use depend upon the severity of the condition and the general
state of the patient's own immune system, but generally range from
about 0.01 to about 100 mg of antibody per dose." (Tso 12: 25-35.)
Principle of Law
"[A] reference may anticipate even when the relevant properties of the
thing disclosed were not appreciated at the time." Abbott Labs. v. Baxter
Pharm. Products, Inc., 471 F.3d 1363, 1367 (Fed. Cir. 2006). Discovery of
a property inherent to a prior art process does not render that process
patentable, even if the prior art did not appreciate the property. Verdegaal
Bros. Inc. v. Union Oil Co., 814 F.2d 628, 633 (Fed. Cir. 1987).
Analysis
The Examiner finds, and Appellants do not contest, that Tso' s
"antibodies [anti-CD3 antibodies mutated in the Fe region to reduce binding
to Fe receptors] may be used to treat rheumatoid arthritis" (Ans. 42; Br. 22
("Tso teaches that these antibodies may be used to treat rheumatoid
arthritis"); see FF11-FF13). The Examiner acknowledges that Tso does not
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discuss "which stage of rheumatoid arthritis may be treated with Tso' s
antibodies" (Ans. 42). The Examiner, however, points to the teachings of
Kraan to evidence "that all rheumatoid arthritis patient[ s] are considered to
have 'chronic joint inflammation' when they first present with clinically
evident disease" (id.). The Examiner reasons that "in treating any patient
with clinically evident rheumatoid arthritis according to the teachings of Tso
one or ordinary skill in the art is necessarily practicing the claimed
invention" (id. at 43).
Appellants, however, contend that "no information is provided by Tso
as to which stage of rheumatoid arthritis may be treated with Tso' s
antibodies" (Br. 22). According to Appellants Kraan teaches "that
rheumatoid arthritis must be treated before it has become chronic" (id. at 22-
23).
We are not persuaded by Appellants' contentions that Tso's disclosure
does not encompass treating chronic joint inflammation in the patient with
rheumatoid arthritis as claimed. As explained by the Examiner, by the time
patients seek treatment for rheumatoid arthritis their condition is already
chronic (FF9). Although Kraan discloses that it may be beneficial to try and
treat the disease early before cartilage destruction (FF 10), we agree with the
Examiner's assessment that "[t]here are no teachings in Kraan 'that
rheumatoid arthritis must be treated before it has become chronic' as
asserted by applicant" (Ans. 42). Indeed, Kraan explains that the condition
is considered chronic long before clinical symptoms appear (FF9) and early
diagnosis would be beneficial for prevention and to mitigate the destruction
of tissue (FFlO). We agree with the Examiner that treating patients having
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rheumatoid arthritis as taught in Tso would necessarily treat chronic joint
inflammation associated with rheumatoid arthritis.
On the record before us, we conclude the Examiner did not err in
rejecting claim 51under35 U.S.C. § 102(b) as anticipated by Tso. Claims
40-44, 46, and 4 7 were not separately argued and fall with claim 51.
SUMMARY
We affirm the rejection of claim 51 under 35 U.S.C. § 103(a) over
Bach, Smith, Hughes, and Malfait. Claims 28-30, 32, 33, 35-37, 40-44,
and 46-48 were not argued separately and fall with claim 51.
We affirm the rejection of claims 14--21, 27, 50, and 52 rejected under
35 U.S.C. § 103(a) over Bach in view of Smith, Hughes, Malfait, and further
in view of Waldmann.
We affirm the rejection of claim 51under35 U.S.C. § 102(b) by Tso
as evidenced by Kraan. Claims 40-44, 46, and 47 were not separately
argued and fall with claim 51.
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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