Ex Parte Tsokos et al

Board of Patent Appeals and Interferences

Jul 6, 2011

10772704 (B.P.A.I. Jul. 6, 2011)

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.
10/772,704 02/05/2004 George C. Tsokos Army 178 5604
30951 7590 07/07/2011
NASH & TITUS, LLC
21402 UNISON RD
MIDDLEBURG, VA 20117
EXAMINER
CHONG, KIMBERLY
ART UNIT PAPER NUMBER
1635
MAIL DATE DELIVERY MODE
07/07/2011 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte GEORGE C. TSOKOS and YUANG-TAUNG JUANG
__________

Appeal 2010-003183
Application 10/772,704
Technology Center 1600
__________

Before TONI R. SCHEINER, LORA M. GREEN and FRANCISCO C. PRATS,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1, 10, 11, 15, 29, and 30, directed to a method of increasing IL-2
production in T cells of a patient with systemic lupus erythematosus. We
have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
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STATEMENT OF THE CASE
Appellants have not presented separate arguments for the claims,
therefore, we select claim 1 as representative of the claimed subject matter.
37 C.F.R § 41.37(c)(1)(vii):
1. A method of increasing IL-2 production in systemic lupus
erythematosus T cells in a patient that has systemic lupus erythematosus
comprising:
administering gene-modified T cells to said patient, said T cells
originating from said patient and having been gene modified by treating
them with antisense cAMP response element modulator (CREM) plasmid
thereby increasing the expression of IL-2 in said T cells in said patient.
The Examiner rejected claims 1, 10, 11, 15, 29, and 30, all the claims
pending, under 35 U.S.C. § 103(a) as unpatentable over Solomou,
1

Weintraub,
2
Monia,
3
Symonds,
4
and Gruenberg.
5

We affirm.
ISSUE
The Examiner finds that Solomou teaches that IL-2 is a growth factor
for T lymphocytes, and is exclusively provided by T cells, and further
teaches that T cells from SLE patients produce decreased amounts of IL-2 as
a result of gene transcriptional repression mediated by the binding of
CREM, a strong repressor of IL-2 production (Ans. 4). According to the

1
Elena E. Solomou et al., Molecular Basis of Deficient IL-2 Production in T
Cells from Patients with Systemic Lupus Erythematosus, 166 J. IMMUNOL.
4216-4222 (2001).
2
Harold M. Weintraub, Antisense RNA and DNA, SCIENTIFIC AMERICAN
40-46 (1990).
3
US 6,159,697, Monia et al., issued December 12, 2000.
4
US 7,345,025 B2, Symonds et al., issued March 18, 2008.
5
US 2003/0134415 A1, Gruenberg, July 17, 2003.
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Examiner, “[a] person of ordinary skill in the art . . . would have recognized
the desirability of increasing IL-2 production by inhibition of the suppressor
protein CREM in SLE patients” (id. at 5). The Examiner concludes that it
would have been obvious to use ex vivo antisense technology to inhibit
expression of CREM in T cells of SLE patients using the techniques
described by Weintraub, Monia, Symonds, and Gruenberg (id. at 4-6).
Appellants contend that Solomou represents “very early work” (App.
Br. 5), “leaves a lot to speculation” (Reply Br. 2), and does not “conclude
that CREM alone is responsible for decreased IL-2 production in SLE
patients” (App. Br. 5). Appellants contend, moreover, that the additional
references cited by the Examiner would not have motivated one of ordinary
skill in the art to use antisense technology to inhibit expression of CREM as
a means of increasing IL-2 production (id. at 6-10).
The issue raised by this appeal is whether Solomou would have
suggested increasing IL-2 production in T cells from SLE patients by
inhibiting expression of CREM, and moreover, whether it would have been
obvious to inhibit expression of CREM using antisense technology.
FACT FINDINGS
The following fact findings are supported by a preponderance of the
evidence of record:
1. Solomou teaches that systemic lupus erythematosus (SLE) “is
a multifactorial autoimmune disease characterized by diverse cellular and
biochemical aberrations, including decreased production of IL-2” (Solomou,
Abstract), resulting in defective regulation of B cell Ig production, which has
a number of consequences and ultimately leads to inflammation, organ
failure, and life-threatening infections (id. at 4216, col. 1).
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2. In normal T cells, “IL-2 gene expression is regulated by the
cooperative binding of discrete transcription factors [AP-1, NF-AT, and
NF-κB] on the IL-2 promoter/enhancer and is predominantly controlled at
the transcriptional level” (Solomou 4216, cols. 1-2).
3. In T cells of SLE patients, however, binding of AP-1 is not
detectable (Solomou 4217, col. 2), and “decreased production of IL-2 is the
result of active IL-2 gene transcriptional repression mediated by the binding
of phosphorylated CREM (p-CREM) to the -180 site of the IL-2 promoter”
(id. at 4216, col. 2). Moreover, binding of p-CREM is not detectable in
normal T cells (id. at 4217, col. 2).
4. Solomou concludes that “p-CREM acts as a repressor of the
IL-2 promoter in SLE T cells” (Solomou 4222), and suggests that “[i]t is
possible that decreased IL-2 production by SLE T cells reflects an integrated
effect of diminished activators (e.g., NF-κB) and excessive expression of
repressors (e.g., p-CREM)” (Solomou 4221, col. 2).
5. Weintraub teaches that antisense RNA can turn off endogenous
cellular genes, e.g., the gene encoding actin in vertebrate cells; the fos, ras,
and cis genes in transformed cells; and the gene encoding cyclin (Weintraub
43, col. 2; 45, col. 2).
6. Monia is directed to antisense compositions and methods for
modulating the expression of a particular human transcription factor, Smad7,
and also discusses antisense techniques and compositions generally (Monia,
col. 3-6).
7. Symonds discusses ex vivo gene therapy involving removing
hematopoietic stem cells from a patient, introducing a gene into the stem
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cells, e.g., a gene directing the synthesis of antisense RNA, and
reintroducing the cells to the patient (Symonds, cols. 13-14).
8. Gruenberg discloses an immunotherapy technique for treating
various diseases, including cancer and SLE (Gruenberg ¶¶ 13-14). The
method involves the steps of: “(i) collecting source material from a subject;
(ii) purifying T-cells from the source material; (iii) activating frequently . . .
and repeatedly . . . the purified T-cells; and optionally (iv) reinfusing the
resulting cells into the same subject or an allogenic recipient” (id. at ¶ 15).
DISCUSSION
We agree with the Examiner that the prior art reasonably suggests the
desirability of increasing IL-2 production by inhibiting expression of the
repressor protein CREM in the T cells of SLE patients, given the fact that
Solomou teaches that decreased production of IL-2 in SLE is the result of
selective, active transcriptional repression mediated by the binding of
phosphorylated CREM (p-CREM) to the -180 site of the IL-2 promoter in
SLE T cells (FF3). Moreover, we agree with the Examiner that it would
have been obvious to use ex vivo antisense technology to inhibit expression
of CREM in T cells of SLE patients, given (a) the fact that Weintraub and
Monia teach that antisense RNA can inhibit expression of targeted genes in a
wide range of cell types, including endogenous genes in vertebrate cells
(FF5, FF6); (b) the fact that ex vivo therapy involving introducing a gene
into a patient’s cells, (e.g., a gene directing the synthesis of antisense RNA),
and reintroducing the cells to the patient was disclosed in the art (FF7); and
(c) the fact that techniques for removing a cell sample from a patient,
purifying T cells from the sample, manipulating the T cells ex vivo, and
reintroducing them into the patient were available (FF8).
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We are not persuaded otherwise by Appellants’ argument that
Solomou “was very early work” (App. Br. 5), “CREM and CREB are
normal compounds found in humans” (id.), and “much was unknown about
the pathways of CREM binding in Lupus patients” (id.), “why CREM bound
to the IL-2 promoter in Lupus patient’s T-cells” (id.), or “how to stop CREM
from binding to the IL-2 promoter” (id.). Nor are we persuaded by the
argument that “[n]one of the cited references . . . conclude that CREM alone
is responsible for decreased IL-2 production in SLE patients” (id.), and “one
of ordinary skill in the art . . . would have understood that multiple
transcriptional factors could be the problem” and “the solution could be
found in addressing the mechanisms that lead to increased pCREM . . . and a
discovery of other positive transcription factors that bind to the IL-2
promoter” (id. at 6).
Solomou unambiguously identifies CREM binding to the IL-2
promoter in the T cells of SLE patients as a significant factor in decreased
IL-2 production in SLE patients (FF3, FF4), and further notes that CREM
binding is not detectable in normal T cells (FF3). It is certainly true that
Solomou teaches that decreased IL-2 production by SLE T cells may be due
to an integrated effect of excessive expression of the repressor CREM,
together with diminished activator binding (FF4). Nevertheless, Appellants
have not explained why one of skill in the art, even without knowing why
CREM selectively binds to the IL-2 promoter in SLE T cells, would not
have wanted to inhibit CREM as part of a comprehensive approach to
increasing IL-2 production in SLE T cells - especially as CREM binding is
not detectable in normal T cells (FF3). In any case, nothing in the present
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claims precludes modulating positive transcription factors in addition to the
repressor.
As for how one would attempt to stop CREM from binding to the IL-2
promoter, we are not persuaded by Appellants’ argument that Weintraub
“only speculates that viral diseases or dangerously mutated oncogenes might
be treated” using antisense technology, and “does not suggest that diseases
wherein defective genes are present in lymphocytes or other naturally
occurring cells of the human body could be treated” using antisense
technology (App. Br. 6-7).
6
Appellants’ characterization of Weintraub’s
teachings is unduly narrow. As discussed above, Weintraub teaches that
antisense technology can be used to turn off endogenous cellular genes, e.g.,
the gene encoding actin, a ubiquitous protein in vertebrate cells (FF5).
Appellants have not explained why one skilled in the art would not expect
antisense technology to be equally effective in inhibiting the gene encoding
CREM.
In addition, Appellants contend that Monia doesn’t disclose or suggest
that antisense modulation would have any effect on IL-2 production in
Solomou’s T cells, or that “administering gene-modified T cells treated with
antisense cAMP response element modulator plasmid would actually
increase the production of IL-2 in patients with SLE” (App. Br. 9).

6
Appellants reproduce isolated excerpts from several references on pages 7-
8 of their Appeal Brief in support of their contention that “the literature at
the time and available to one of ordinary skill actually taught against” using
antisense technology. Appellants have not explained the relevance of these
references to ex vivo use of antisense compounds, nor have the underlying
references been made of record. Accordingly, we will not address them
further.
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Similarly, Appellants contend that Symonds “is not directed to the claimed
highly complex immunological T cells” and “did not solve the mystery of
why CREM is increased in SLE T cells or whether there were other
transcriptional factors that effect IL-2 production or why CREM production
decreased in SLE patients following stimulation” (id.). Finally, Appellants
contend that Gruenberg’s approach “is very different than the present
invention” (id. at 10), which corrects the T-cells not just activates them”
(id.), and “[m]ore importantly, does not overcome Symonds, Monia, and
Weintraub[’]s lack of teaching that CREM is the only reason that IL-2
production is decreased in SLE patients” (id.).
Appellants’ arguments are not persuasive. As discussed above, the
concept that CREM binding to the IL-2 promoter in the T cells of SLE
patients is a significant factor in decreased IL-2 production in SLE patients,
and that decreased IL-2 production by SLE T cells is due, in significant part,
to excessive expression of CREM, comes from Solomou. The Weintraub,
Monia, Symonds, and Gruenberg references were not cited to confirm or
expand Solomou’s conclusions regarding the relationship between excessive
expression of CREM and decreased IL-2 production, but simply to show that
ex vivo antisense techniques for modulating protein expression were known,
as were specific techniques for isolating T cells from a patient, manipulating
the cells, and reintroducing them.
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CONCLUSION
The evidence of record is sufficient to support the Examiner’s
conclusion that Solomou would have suggested increasing IL-2 production
in T cells from SLE patients by inhibiting expression of CREM, and that it
would have been obvious to inhibit expression of CREM in cells isolated
from SLE patients using antisense technology.
SUMMARY
We affirm the rejection of claims 1, 10, 11, 15, 29, and 30 under
35 U.S.C. § 103(a) as unpatentable over Solomou, Weintraub, Monia,
Symonds, and Gruenberg.
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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