Ex Parte Noelle et al

Board of Patent Appeals and Interferences

Sep 24, 2009

09164568 (B.P.A.I. Sep. 24, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte RANDOLPH J. NOELLE, TERESA M. FOY, and
FIONA H. DURIE
____________

Appeal 2009-003956
Application 09/164,568
Technology Center 1600
____________

Decided: September 24, 2009
____________

Before RICHARD M. LEBOVITZ, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal by the patent applicants from the
patent Examiner’s rejection of claims 82-94 under 35 U.S.C. 103(a). The
Board’s jurisdiction for this appeal is under 35 U.S.C. § 6(b). We reverse.

Appeal 2009-003956
Application 09/164,568

STATEMENT OF THE CASE
The claims are to methods “for reducing antigen-specific T cell
responsiveness in vivo” comprising administering (a) an antigen presenting
cell (“APC”) expressing an autoantigen; and (b) an anti-gp39 antibody.
Gp39 is a ligand for CD40, a protein found on the surface of B cells (Spec.
2:23-29). Gp39 is expressed on activated, but not resting T cells (id. at 2:30-
31). The gp39 protein, when expressed on the T cell surface, can trigger B
cell proliferation and antibody production (id. at 2:33-36). The
Specification states that
it has been discovered that, under appropriate conditions,
interference of an interaction between gp39 on a T cell and a
ligand on a cell which is presenting antigen to the T cell [an
APC, such as a B cell] can induce antigen-specific T cell
tolerance. Accordingly, the cell which presents antigen to the T
cell requires an interaction between a gp39 ligand (e.g., CD40)
on the cell and gp39 on the T cell to be able to provide signals
necessary for activation of the T cell. Inhibition of the
interaction between the gp39 ligand and gp39 [with an anti-
gp39 antibody] prevents T cell activation and rather induces
antigen-specific T cell tolerance.
(Spec. 3:7-14.)
All pending claims 82-94 stand rejected by the Examiner under 35
U.S.C. § 103(a) as obvious in view of Lederman (US 6,403,091 B1, Jun. 11,
2002), Beschorner (US 5,597,563, Jan. 28, 1997), Eynon (Small B Cells as
Antigen-presenting Cells in the Induction of Tolerance to Soluble Protein
Antigens, 175 J. EXP. MED. 131-138 (1992)), and Cobbold (US 5,690,933,
Nov. 25, 1997) (Ans. 4).
Claim 82, the only independent claim on appeal, is representative and
reads as follows:
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82. A method for reducing antigen-specific T cell
responsiveness in vivo, which method comprises administering
to a subject in need of such treatment:
(a) an antigen-presenting cell that presents an autoantigen
to an activated T cell expressing mouse or human gp39; and
(b) an anti-gp39 antibody which binds to mouse or
human gp39 on the activated T cell,
wherein the anti-gp39 antibody is administered prior to,
concurrent with, or subsequent to administration of the antigen-
presenting cell in an amount effective to reduce T cell
responsiveness to the antigen-presenting cell.

STATEMENT OF ISSUE
Claim 82 is directed to a method “for reducing antigen-specific T cell
responsiveness in vivo” comprising administering (a) an APC expressing an
autoantigen; and (b) an anti-gp39 antibody. Citing Beschorner and Eynon
for teaching APC administration, Lederman for its teaching of an anti-gp39
antibody, and Cobbold for a combination of antigen and antibody, the
Examiner concluded that the claimed invention would have been obvious to
a person of ordinary skill in the art. Appellants contend that the Examiner
erred in failing to cite references or general knowledge that would suggest or
motivate the ordinary skilled worker to have combined the references to
arrive at the claimed invention (App. Br. 10). The issue in this appeal is
whether Appellants established that the Examiner erred in finding a reason
to have combined the cited prior art.

PRINCIPLES OF LAW
A factfinder should be aware, of course, of the distortion caused
by hindsight bias and must be cautious of arguments reliant
upon ex post reasoning. See Graham, 383 U.S., at 36, 86 S.Ct
684 (warning against a “temptation to read into the prior art the
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teachings of the invention in issue” and instructing courts to “
‘guard against slipping into the use of hindsight’ ” (quoting
Monroe Auto Equipment Co. v. Heckethorn Mfg. & Supply Co.,
332 F.2d 406, 412 (C.A.6 1964))). Rigid preventative rules that
deny factfinders recourse to common sense, however, are
neither necessary under our case law nor consistent with it.
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).

SCOPE AND CONTENT OF THE PRIOR ART
When making an obviousness determination, the scope and content of
the prior art must first be ascertained. Graham v. John Deere Co., 383 U.S.
1, 17 (1966). The following numbered facts (“F”) summarize the prior art
relied upon the Examiner in setting forth the basis of the rejection.

The Lederman patent
1. Lederman teaches that resting T cells contact antigen primed B cells (or
other APCs) resulting in the T cell becoming activated (col. 1, ll. 28-54).
Activated T cells cause B cells to differentiate into antibody secreting cells
(col. 1, ll. 35-42; col. 2, ll. 8-12; Spec. 1:17-36).
2. Lederman describes a monoclonal antibody, 5c8, which binds to the
CD40 ligand located on the surface of activated T cells, thereby inhibiting
“T cell activation of B cells.” (Col. 2, ll. 15-21.)
3. Lederman states that the antibody binds to T cells which are interacting
with B cells in the lymph nodes, and does not bind to other T cells (col. 7, ll.
7-9). By binding to the CD40 ligand on the T cell surface, the antibody
inhibits B cell activation (id. at 7:10-14).
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4. Methods are described by Lederman of inhibiting the immune response
of an animal by administering an effective amount of the antibody (col. 11,
8-40).
5. In one embodiment, Lederman teaches “inhibiting the autoimmune
response in an animal suffering from autoimmune disease.” (Col. 11, ll. 40-
49.)
The Beschorner patent
6. Beschorner describes its invention as a “method of inducing antigen-
specific tolerance in an animal.” (Col. 4, ll. 35-36.) The “method entails
treatment of an animal with an immunosuppressant agent under conditions
sufficient to deplete the thymic medulla, or thymic equivalent, of antigen
presenting cells, followed by infusion of dendritic cells which are
tolerogenic for the antigen.” (Col. 4, ll. 36-41.)
7. The antigen to which tolerance is desired is displayed on the APC surface
for presentation to the T cell (col. 6, ll. 49-65).
8. The immunosuppressive agent is defined by Beschorner as “an agent
which depletes the thymic medulla of APCs, such as dendritic cells.” (Col.
8, ll. 1-3.)
9. The immunosuppressive agents induce depletion of APCs from the
thymus (col. 8, ll. 31-33).
Physiologically, one role of these cells is to act in a “barrier-
like” manner between the cortex and the medullary regions of
the thymus. In this role, these cells prevent the transit of
immature conical [sic, cortical] thymocytes from the cortex out
of the thymus. However, upon depletion of the APCs from the
medulla this barrier function becomes impaired and, as a result,
cortical thymocytes appear in extra-thymic regions, such as the
peripheral blood. Thus, it is possible to monitor the
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effectiveness of an immunosuppressive agent of the invention
simply, for example, by detecting the increase of
immature thymocytes in the peripheral blood. (Col. 8, ll. 34-46.)
10. After the immunosuppressant is administered, the animal is infused with
“donor dendritic cells [acting as APCs] . . . able to induce tolerance to donor
antigens carried on the surface of the dendritic cell. The donor dendritic cells
will re-populate the thymus of the recipient host and re-program the host T-
cells to be tolerant of donor antigens of the donor” tissue (col. 8, ll. 55 to col.
9, l. 5).
Eynon
11. Eynon teaches that resting B cells, acting as antigen-presenting cells, are
able to induce tolerance to soluble protein antigens in mice (Abstract).
12. Eynon proposes “that presentation of antigen by a small, resting B cell
to a small resting T cell is tolerogenic and results in loss of T cell activity.”
(P. 131, col. 2.)
13. Eynon does not administer the B cells to animals, but rather administers
to mice a soluble protein antigen which is processed by B cells (p.132, 1st
full paragraph; p. 135, “Discussion”). After antigen administration, the mice
become tolerant to the antigen (id.).
The Cobbold patent
14. Cobbold describes producing tolerance in an animal by administering
“non-depleting” CD4 and CD8 antibodies which reduce the population of
certain T cells (Abstract; col. 1, l. 45 to col. 2, l. 66).
15. Antigen may be administered with the antibodies because “[p]ersistant
[sic] antigen is required to maintain tolerance.” (Col. 3, ll. 56-60.)
“Tolerance can therefore be induced to an antigen in a host by administering
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non-depleting CD4 and CD8 mAbs and, under cover of the mAbs, the
antigen.” (Col. 3, ll. 44-46.)
CLAIM INTERPETATION
16. Claim 82 is to a method of reducing antigen-specific T cell
responsiveness in vivo. The method comprises administering two
components to a subject:
17. “(a) an antigen-presenting cell that presents an autoantigen to an
activated T cell expressing mouse or human gp39; and”
18. “(b) an anti-gp39 antibody which binds to mouse or human gp39 on the
activated T cell.”
19. An “autoantigen” would be understood by persons of ordinary skill in
the art to mean a self-antigen which is a normal constituent of the subject’s
body. (Beschorner, col. 5, ll. 51-57.) The Specification states that reducing
T cell responsiveness to an autoantigen is useful for treating an autoimmune
disease (Spec. 14: 1-3).
20. Gp39 is a protein expressed on the surface of T cells which acts as a
ligand for the CD40 protein on B cells (Spec. 2:23-36; 3:2-14). Gp39 is also
known as the CD40 ligand (id. at 2:27-28).
21. Claim 82 recites (a) an APC “that presents an autoantigen to an
activated T cell” which expresses gp39. We interpret this to mean that the
APC is “capable” of presenting the autoantigen to an activated T cell, and
therefore T cell antigen presentation is a functional property of the APC.
However, the claim does not positively recite a step in which the APC is
administered to the activated T cell. Rather, the method comprises
“administering to a subject” the APC component; it does not recite that the
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APC is administered to an activated T cell or to a subject with activated T
cells.

DIFFERENCES BETWEEN THE CLAIMED INVENTION AND THE
PRIOR ART
Once the scope and contents of the prior art have been determined, the
differences between the prior art and the claimed invention must be
identified. Graham, 383 U.S. at 17. The following facts are relevant to this
determination:
22. Lederman describes a method of inhibiting an autoimmune response by
administering an antibody which binds to the CD40 ligand on the surface of
activated cells (F1-2). The CD40 ligand is the same protein as gp39 (F20).
Appellants do not dispute that Lederman’s antibody meets the limitation of
the claimed “(b) . . . anti-gp39 antibody.”
23. Lederman does not disclose administering the (b) anti-gp39 antibody
with “(a) an antigen-presenting cell that presents an autoantigen to an
activated T cell expressing” gp39 as in claim 82.
24. Beschorner describes inducing tolerance with APCs (dendritic cells) that
present a self antigen to T cells, along with an immunosuppressive agent
(F6-10). Appellants do not dispute that Beschorner’s APCs meet the
claimed limitation of (a) “an antigen-presenting cell” that is able to present
an autoantigen to an activated T cell.
25. Eynon teaches that resting B cells, acting as antigen-presenting cells, are
able to induce tolerance to soluble protein antigens in a subject (F11-13).
26. Neither Beschorner nor Eynon describe administering the APC in
combination with an anti-gp39 antibody as claimed in claim 82.
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27. Cobbold describes administering antibodies to T cells and an
autoantigen (F14-15), but not anti-gp39 and not autoantigen in the form of
an APC.
REASON TO COMBINE THE PRIOR ART
Having established the differences between the prior art and the
claimed invention, the next step is to identify a reason why persons of
ordinary skill in the art would have been prompted to combine the prior art
to have made the claimed invention. KSR, 550 U.S. at 418.
28. The Examiner found that Cobbold teaches antibodies directed to CD4-
expressing T cells, which are the same T cell subpopulation targeted by
Lederman’s gp39 antibodies (Ans. 16).
29. The Examiner also found that Cobbold teaches administration of self-
antigen to produce tolerance, but not as an APC (id.).
30. However, the Examiner found that “Beschorner teaches an alternative
means (antigen-presenting cells) to provide persistent antigen, antigen
reminders or antigen of interest at the time of administering
immunosuppressive agents, such as immunosuppressive anti-T cell
antibodies.” (Id.)
31. The Examiner concluded that the ordinary skilled worker
would have been motivated to select the combination of an
autoantigen containing antigen presenting cells [the Beschorner
APCs] and a gp39-specific antagonist [the Lederman antibody]
to induce antigen-specific non-responsiveness to autoantigens
as a treatment for autoimmunity by providing persistent
autoantigens under the cover of immunosuppressives, since
both contribute to long term antigen non-responsiveness in the
treatment of autoimmunity.
(Ans. 6.)

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ANALYSIS
The disputed issue in this appeal is whether persons of ordinary skill
in the art would have had reason to combine Lederman’s anti-gp39
antibodies with Beschorner’s APCs to reduce antigen-specific T cell
responsiveness as required by claim 1.
The Examiner found that while the claimed combination of an anti-
gp39 antibody and autoantigen presenting APC was not disclosed in the
prior art, both components were known to the ordinary skilled worker as
evidenced by Lederman and Beschorner, respectively, and had been used to
induce antigen tolerance (F4, 6, 22-24) and thus would have been obvious to
combine (F31). The Examiner also found that an antibody/antigen
combination had been taught by Cobbold as useful for inducing tolerance
(F14, 15). Based on this teaching, the Examiner reasoned that it would have
been obvious to have utilized Lederman’s antibody in place of Cobbold’s
antibody, and Beschorner’s antigen presenting cell in place of Cobbold’s
antigen in order to induce antigen tolerance (F28-31).
Appellants challenged the Examiner’s case as lacking a reason to
combine. They contend that the mechanisms and cell populations described
in Lederman, Beschorner, and Cobbold differ and therefore there would
have been no motivation to have combined the references. To resolve this
dispute, we must turn to the facts.
Lederman described using a monoclonal antibody targeted against
activated T cells to inhibit the immune response (F1-5). Lederman’s
antibody inhibited the B cell (acting as an APC) from activating the T cell
(F2). In Beschorner, the T-cells are re-programmed “to be tolerant of donor
antigens” by autoantigen presenting APCs (the same type as claimed)
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administered after a step in which the host thymus is depleted of APCs (F6-
10). Therefore, as argued by Appellants, Lederman and Beschorner utilized
different approaches to achieve the same end of reducing T cell
responsiveness: Lederman administered antibodies; Beschorner provided
antigen presenting cells.
Moreover, in Beschorner’s system, dendritic APCs are infused into
the subject where they interact with and produce autoantigen tolerance in the
subject’s T cell population (F6, 7, & 10). On the other hand, Lederman’s
goal is inhibit the interaction between the APC and T cell populations (F2 &
3). The Examiner did not establish a reason to have utilized Lederman’s
inhibitory antibody in a system aimed at promoting the T cell/APC
interaction.
Appellants also argue that different T cell populations were treated in
Lederman and Beschorner, respectively. Appellants contend that Lederman
targeted activated T cells, while Beschorner’s target was immature T cells
(App. Br. 61). According to Appellants, the thymus in Beschorner’s subject
was depleted of APCs (id.). T cells become activated by APCs (F1).
Therefore, Appellants assert, T cell activation would have been prevented in
Beschorner (App. Br. 6).
Appellants’ argument is logical as to why T cell activation would be
prevented by APC depletion. However, there is insufficient evidence that
the subject in Beschorner would have been completely devoid of activated T

1 Appellants also contend that the claims require administration of the anti-
gp39 to an activated T cell. This interpretation is narrower than the claim
language dictates. The claims do not require that the APC is administered to
an activated to T cell or a subject having activated T cells (F21).

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cells immediately prior to or after APC administration. Nonetheless,
Beschorner does not identify the specific class of T cells treated by its
method nor did the Examiner establish that Beschorner targeted activated T
cells. Therefore, we conclude that it would have been uncertain that
Beschorner’s treated T cell population was the same as Lederman’s.
In view of the apparent differences between Beschorner and
Lederman – in both mechanism and targeted T cell populations – we
conclude that the ordinary skilled worker would not have had adequate
reason to combine the references in the manner suggested by the Examiner.
Eynon was also cited by the Examiner as a reason to have utilized
APCs in combination with an anti-gp39 antibody to reduce antigen-specific
T cell responsiveness as recited in claim 82. However, although Eynon’s
investigation does ascribe tolerogenic activity to antigen-presenting B cells,
Eynon did not induce tolerance by actually administering the APCs (F13).
In contrast, Beschorner actually administered APCs to induce tolerance, but
disclosed that doing so requires administration of an immunosuppressive
agent to deplete the subject’s thymic medulla of APCs (F6, 8).
Eynon also explicitly teaches that it treats a “resting T cell” (F12), not
an activated T cell as in Lederman (F2-3). Thus, Eynon and Lederman were
concerned with different T cell targets.
For these reasons, we are not persuaded that a person of ordinary skill
in the art would have combined such a process with Lederman’s method.
Given Eynon’s failure to describe inducing tolerance by administering APCs
and its concern with a different cell population than taught in Lederman, we
are not persuaded that Eynon bolsters the Examiner’s posited combination of
Lederman and Beschorner.
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In sum, neither the teachings in Beschorner nor Eynon would have
been combined with Lederman by persons of ordinary skill in the art. The
Examiner appeared to have been guided by hindsight.
The Examiner also found it obvious to have substituted Cobbold’s
non-depleting antibodies for Lederman’s anti gp39. Again, we do not find
sufficient evidence to support the reasonableness of the combination.
Cobbold’s antibodies were to reduce a T cell population (F14). Lederman’s
were to directed to activated T cells to inhibit the T cell from activating B
cells (F1). The prior art references were concerned with different antibodies,
targeting not only different molecules (CD4/CD8 vs. gp39) but also having
different effects on the cells (reducing the cell population vs. preventing an
interaction) (App. Br. 12). Consequently, we discern no logical reason to
have combined Lederman with Cobbold.

CONCLUSION OF LAW & SUMMARY
The Examiner erred in concluding that the method recited in claim 82
would have been obvious to persons of ordinary skill in the art in view of
Lederman, Beschorner, Eynon, and Cobbold. The obviousness rejection of
claim 82, and dependent claims 83-94, is reversed.

REVERSED

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