Ex Parte Bach et al

Patent Trial and Appeal Board

Sep 23, 2016

11266959 (P.T.A.B. Sep. 23, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
11/266,959 11104/2005 Jean-Francois Bach
27162 7590 09/26/2016
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.
695458-108 1505
EXAMINER
SKELDING, ZACHARY S
ART UNIT PAPER NUMBER
1644
MAILDATE DELIVERY MODE
09/26/2016 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 JEAN-FRANCOIS BACH and LUCIENNE CHATENOUD1
Appeal2015-002757
Application 11/266,959
Technology Center 1600
Before ERIC B. GRIMES, JOHN G. NEW, and TIMOTHY G. MAJORS,
Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to methods
of treating psoriasis by administering non-mitogenic anti-CD3 antibodies.
The claims have been rejected as obvious. We have jurisdiction under 35
U.S.C. § 6(b).
We affirm.
1 Appellants identify the Real Party in Interest as the Institute National de la
Sante et de la Recherche Medicale. (Br. 1.) Appellants further identify
GlaxoSmithKline as a licensee under the application. (Id.)
Appeal2015-002757
Application 11/266,959
STATEMENT OF THE CASE
According to the Specification, "[t]he invention relates to a method
for treating established and ongoing spontaneous auto-immune diseases in
mammals." (Spec. 1.) More specifically, "mAbs [monoclonal antibodies]
directed against the CD3 complex of the T cell receptor have been shown to
cause transient T-cell depletion and antigenic modulation of the CD3-T cell
receptor complex." (Id.) Appellants disclose "permanent antigen-specific
unresponsiveness obtained with said anti-CD3 active principles make them
particularly useful as therapeutic tools for treating auto-immune pathologies.
In particular, they are suitable for treating diabetes, rheumatoid arthritis,
multiple sclerosis or psoriasis." (Spec. 3.)
Claims 16-25 are on appeal. Claim 16 is illustrative:
16. A method of treating an ongoing autoimmune disease in a
human having said disease, wherein said disease is psoriasis,
compnsmg:
treating said human by administering one or more non-
mitogenic anti-CD3 active compounds selected from the group
consisting of anti-CD3 antibodies and fragments of
anti-CD3 antibodies in an amount effective to treat said psoriasis.
(Br. 10 (Claims App'x).)
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The claims stand rejected as follows:
I. Claims 16-25 under 35 U.S.C. § 103(a) over Smith2 in view of de
Jong, 3 Asadullah,4 Griffiths,5 Rocken, 6 Chatenoud,7 Chatenoud II, 8
Uyemura,9 and Nickoloff. 10
2 Judith A. Smith et al., T cell inactivation and cytokine deviation promoted
by anti-CD3 mAbs, 9 CURRENT OPINION IN IMMUNOLOGY 648-654 (1997)
("Smith").
3 Ro lien de Jong et al., Selective stimulation of T helper 2 cytokine responses
by the anti-psoriasis agent monomethylfumarate, 26 EUR. J. IMMUNOL.
2067-2074 (1996) ("de Jong").
4 Khusru Asadullah et al., Influence of monomethylfumarate on monocytic
cytokine formation - explanation for adverse and therapeutic effects in
psoriasis? 289 ARCH DERMATOL. RES 623-630 (1997) ("Asadullah").
5 Christopher E. 1\1. Griffiths et al., Psoriasis, T cells and autoimmunity, 89
JOURNAL OF THE ROYAL SOCIETY OF MEDICINE 315-319 (1996)
("Griffiths").
6 Martin Rocken et al., The Role of THI And TH2 Dichotomy: Implications
For Autoimmunity, 64 REV. RHUM. 131S-137S (1997) ("Rocken").
7 Lucienne Chatenoud et al., CD3 Antibody-Induced Dominant Self
Tolerance in Overtly Diabetic NOD Mice, 158 THE JOURNAL OF
IMMUNOLOGY 2947-2954 (1997) ("Chatenoud").
8 L. Chatenoud, Biological Immunosuppressants: The Way to Clinical
Transplantation Tolerance, 29 TRANSPLANTATION PROCEEDINGS 51-55
(1997) ("Chatenoud II").
9 Koichi Uyemura et al., The Cytokine Network in Lesional and Lesion-Free
Psoriatic Skin Is Characterized by a T-Helper Type 1 Cell-Mediated
Response, 101 J. INVEST. DERMATOL. 701-705 (1993) ("Uyemura").
10 Brian J. Nickoloff et al., Keratinocyte Interleukin-I 0 Expression Is
Upregulated in Tape-Stripped Skin, Poison Ivy Dermatitis, and Sezary
Syndrome, but Not in Psoriatic Plaques' 73: 1 CLINICAL IMMUNOLOGY AND
IMMUNOPATHOLOGY 63-68 (1994) ("Nickoloff').
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Application 11/266,959
II. Claims 16-19 and 23-25 under 35 U.S.C. § 103(a) over Hughes 11
in view of de Jong, Asadullah, Griffiths, Rocken, Chatenoud, Chatenoud II,
Uyemura, and Nickoloff.
III. Claims 20-22 under 35 U.S.C. § 103(a) over Hughes in view of
de Jong, Asadullah, Griffiths, Rocken, Chatenoud, Chatenoud II, Uyemura,
and Nickoloff, and further in view of Alegre. 12
DISCUSSION
Issue
On appeal, we determine whether the Examiner's conclusion that the
claims would have been obvious under Rejections I-III (as described above)
is supported by a preponderance of the evidence.
As summarized below, because the same issue is dispositive for each
of Rejections I-III, we address the rejections together.
Appellants do not challenge the Examiner's finding that the prior art
(e.g., Smith) teaches "non-mitogenic anti-CD3 antibodies, i.e., FcR-
nonbinding anti-CD3 antibodies, and non-mitogenic anti-CD3 fragments ...
modulate the activity of the T-cells to which they bind by suppressing the
production of Thl-type cytokines." (Ans. 3.) Similarly, Appellants do not
11 Catherine Hughes et al., Induction of T Helper Cell Hyporesponsiveness in
an Experimental Model of Autoimmunity by Using Nonmitogenic Anti-CD3
Monoclonal Antibody, 153 THE JOURNAL OF IMMUNOLOGY 3319-3325
(1994) ("Hughes").
12 Maria-Luisa Alegre et al., Effect Of A Single Amino Acid Mutation On The
Activating And Immunosuppressive Properties Of A "Humanized" OKT3
Monoclonal Antibody, 148 THE JOURNAL OF IMMUNOLOGY 3461-3468
(1992) ("Alegre").
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Application 11/266,959
challenge the Examiner's finding that the prior art teaches, for multiple
autoimmune disease models characterized by over-production of Thl-type
cytokines, "that administration of a non-mitogenic anti-CD3 antibody ...
[or] fragment effectively treats disease by suppressing the production of
Thl-type cytokines - IFN-y and IL-2 - thereby favoring the production of
Th2-type cytokines." (Id.)
The dispute - and thus the issue - is whether the evidence of record
would have taught or suggested to the skilled artisan at the time of invention
that psoriasis was an autoimmune disease mediated by Thl cells. According
to Appellants, "even at the time of [Appellants'] earliest filing date
[December 5, 1997], those of ordinary skill in the art ... had expressed
doubts, and therefore were uncertain as to whether psoriasis [was] a Th 1-
mediated disease." (Br. 3.) In support, Appellants cite the teachings of
Vollmer13 and McFarland, 14 along with a handful of excerpts from certain art
cited by the Examiner. (Id. at 3-7.) Because of the alleged uncertainty
about a connection between psoriasis and Thl cytokines, Appellants contend
"those of ordinary skill in the art would not expect reasonably that the
administration of a non-mitogenic anti-CD3 antibody would be successful in
treating psoriasis." (Id. at 7.)
13 Sigrid Vollmer et al., T lymphocytes derived from skin lesions of patients
with psoriasis vulgaris express a novel cytokine pattern that is distinct from
that of T helper type 1 and T helper type 2 cells, 24 EUR. J. IMMUNOL. 2377-
2382 (1994) ("Vollmer").
14 Henry F. McFarland, Complexities in the Treatment of Autoimmune
Disease, 274 SCIENCE 2037-2038 (1996) ("McFarland").
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Findings of Fact (FF)
FF 1. The Examiner's findings of fact and statement of Rejections I-
HI may be found at pages 2-5 of the Non-Final Action dated May 30, 2013.
We adopt those findings and provide the following for emphasis.
FF 2. Smith teaches
Th 1 cells secrete the pro-inflammatory cytokines TNF -a, IFN-y,
and IL-2, whereas Th2 cells secrete 'anti-inflammatory' or pro-
humoral response cytokines such as IL-4, IL-5, IL-10 and IL-13.
These Th cell subsets cross-regulate each other in that Th2
cytokines promote Th2 responses and differentiation but
suppress Thl responses and differentiation, and vice versa.
(Smith 651.)
FF 3. Smith also teaches "treatment with anti-CD3 F(ab')2 mAbs
suppressed the T cell production of IL-2 and IFN-y, without affecting IL-4
production .... These findings are consistent with a model of selected Thl
suppression by nonmitogenic anti-CD3 rru:L\-.bs." (Id.; see also Hughes 3319
("Thl cell hyporesponsiveness with nmCD3 [nonmitogenic anti-CD3 mAb]
can significantly alter the course of CIA [collagen-induced arthritis] and
suggest that IL-2 and/or IFN-y play a crucial role in disease pathogenesis.");
see also Chatenaud 2953.)
FF 4. de Jong teaches "[t]ype 2 cytokines are thought to have a
protective role in psoriasis vulgaris by dampening the activity of T helper 1
(Thl) lymphocytes." (de Jong Abstract.) de Jong further teaches "the anti-
psoriatic agent MMF [ monomethylfumarate] can selectively up-regulate IL-
4 and IL-5 [i.e., Th2 cytokines] secretion by human T-cells" (id. at 2072)
and "[n]either IL-2 nor IFN-y [Thl cytokines] was modulated by MMF" (id.
at 2069). de Jong describes "regulatory effects of MMF ... provide a
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mechanistic explanation for the beneficial effects of MMF in psoriasis, a
presumably Thl-associated autoimmune skin disorder." (Id. at 2072.) de
Jong teaches "Thl T cells and cytokines are also thought to be involved in
the pathogenesis of psoriasis vulgaris .... A polarized Thl cytokine
secretion profile in T cell clones established from skin lesions of psoriasis
patients has been described[], although such a clear segregation was not
found in other studies." (Id. at 2073.)
FF 5. Asadullah teaches "[b]ecause of predominant expression of
interleukin-2 (IL-2[)] and interferon gamma (IFN-y), but a lack of IL-4 in
the skin lesions, psoriasis is believed to be characterized by a type 1
cytokine pattern." (Asadullah 623.)
FF 6. Griffiths teaches "[t]here is little doubt that T cells, whatever
their phenotype, within plaques of psoriasis ... secrete cytokines recognized
as synonymous with lymphocyte activation-i.e. IL-2 and interferon-y."
(Griffiths 315.) According to Griffiths, "[p ]laques of psoriasis chiefly
contain IL-2 and interferon-y, thus indicating a Th1 profile disease." (Id.)
Griffiths teaches "[ u ]ntil the antigen in psoriasis is described,
immunomodulation of the psoriatic process could be achieved by ...
biological response modification-suppressing or normalizing the Th1
profile of psoriasis." (Id. at 318.) Griffiths also discloses "[t]he exact
combinations of cytokines or growth factors necessary for subsequent T -
cell-driven keratinocyte proliferation are still uncertain but are consistent
with a Th1 profile in which interferon-y is a vital component." (Id.)
FF 7. Rocken teaches "autoimmune diseases such as psoriasis ...
frequently exacerbate during therapy with proinflammatory cytokines,
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especially IFN-a [a Thl cytokine]." (Rocken 134S.) Rocken also teaches
"during an early phase of melanoma therapy with IL-4, it became evident
that this [Th2] cytokine has little effect on tumor progression, but was very
helpful in the treatment of psoriasis." (Id. at 136S.)
FF 8. Uyemura teaches "results indicate that psoriatic lesions have a
type 1 cytokine profile (i.e., interleukin[IL ]-2, interferon[IFN]-y, and tumor
necrosis factor[TNF]-a, without a significant component of type 2 cytokines
(i.e., IL-4, IL-5, and IL-10)." (Uyemura Abstract; see also id. Table 1, Fig.
1.)
FF 9. Nickoloff teaches "[ o ]ne group exemplified by psoriasis is
characterized by consistently detectable mRNAs for IL-2, IFN-y, and TNF-
a, but not IL-4, IL-5, IL-10, thereby closely resembling the murine Thl-type
cell-mediated response." (Nickoloff Abstract.)
Analysis
The Examiner finds "the vast majority of the prior art teachings point
to psoriasis as a disease where Thl-type cytokines like IFN-y play a critical
role in pathogenesis, and where immunomodulation toward Th2-type
cytokines was expected to be therapeutic." (Ans. 7.) Moreover, as the
Examiner notes, several of the references cited by the Examiner were
published after Vollmer, yet do not embrace Vollmer's conclusion that "the
immune reaction in psoriasis cannot be reconciled with a THI or TH2
response." (Ans. 12 (quoting Vollmer 2382).)
Further as to Vollmer, the Examiner finds the experimental methods
Vollmer describes were less rigorous and the results less compelling
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compared to other applied art, such as Uyemura. For example, according to
the Examiner,
Uyemura describes in great detail the many steps they took to
ensure their RT-PCR and radioactive hydridization assays
reflected accurate quantitative results (see page 702, "PCR,"
"Radioactive Hybridization ... " and "Validity of PCR.") ...
[including] efforts to ensure that the PCR limiting constituent
was the cDNA itself not the PCR reagents.
(Ans. 9-10.) In contrast, the Examiner finds "Vollmer gives no details about
how, or even if, they ensured the amount of cDNA template being used was
the rate-limiting variable of their PCR reaction." (Id. at 11 (emphasis
omitted).) In addition, the Examiner finds
while the teachings of Vollmer emphasize the pattern they detect
in psoriatic skin ... is neither Thl or Th2 biased (see abstract),
three members of the pattern - IFN-y, IL-2 and the absence of
IL-4 - are clearly Thl biased, TGF-B expression is irrelevant
because, in contrast to all the other cytokines measured in
Vollmer, it is expressed in biopsies from normal skin ... and the
only cytokine which conflicts with a clear Thl-bias - IL-5 - is
detectable only when Vollmer uses their highest sensitivity
probe.[ 15]
In sharp contrast to Table 1 of Uyemura ... Vollmer did not, and
could not make quantitative comparisons between most
cytokines they deemed to be expressed (see Vollmer Table 1 ).
15 Insofar as Vollmer suggests the expression of IL-5 in its experiment is
inconsistent with a Thl immune response("[ o ]ur data thus demonstrate that
inflammation in psoriasis involves a distinctive type of cellular immune
reaction ... [with] the combined expression ofIFN-y, TNF-B and IL-2 with
IL-5"), Vollmer acknowledges "[ u ]nfortunately, a reliable detection system
for IL-5 is not available at present." (Vollmer 2381 (emphasis added).)
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Rather, Volhner merely indicates if expression of a cytokine
was I was not detected by their probes ( + or -) ....
(Id. at 11-12.)
As noted above, Appellants argue disclosures in Vollmer, McFarland,
de Jong, and Griffiths show uncertainty about whether psoriasis was a Thl-
mediated disease. (Br. 3-7.) Thus, Appellants' argument goes, the skilled
artisan would not have predictably treated psoriasis with nonmitogenic anti-
CD3 antibodies, which are known to suppress Thl cell production of IL-2
and IFN-y cytokines. (Br. 7; see also FF 2-3.)
The Examiner has the better position, and the preponderance of the
evidence favors the conclusion that the claims would have been obvious.
We discuss further below.
Appellants highlight a portion of a sentence from de Jong, which
reads "although such a clear segregation [between a Thl and Th2 immune
response] was not found in other studies." (Br. 3) This does not, however,
help Appellants' argument. There are two "other studies" cited by de Jong,
and one is Vollmer. The highlighted portion of de Jong merely recognizes
that the scientific community did not unanimously identify psoriasis as likely
being a Thl-mediated disease. In context, however, it is clear that de Jong is
citing Vollmer as an outlier. Like other references of record that post-date
the publication of Vollmer (see, e.g., Griffiths, Asadulla, Rocker), de Jong
strongly suggests that psoriasis is a Thl-mediated disease. (FF 4-7.) For
example, de Jong teaches that "[t]ype 2 cytokines are thought to have a
protective role in psoriasis vulgaris by dampening the activity of T helper
(Th 1) lymphocytes" and psoriasis is "presumably [a] Th I -associated
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autoimmune disorder." (FF 4.) And rather than act on Vollmer's call "for a
revision and reformulation of the TH1/TH2 nomenclature" relative to
psoriasis (Vollmer 2382), de Jong and other post-Vollmer references
continued to treat psoriasis as a Thl-mediated disease. (Ans. 12.) Indeed,
Appellants have not provided evidence of a single reference among the body
of scientific literature that has adopted Vollmer' s conclusion.
Appellants also cite portions of McFarland, which Appellants contend
shows further doubt among the scientific community that existed prior to the
filing of the present application. (Br. 7.) We are not persuaded. McFarland
is general in nature; its teachings are silent about psoriasis. That McFarland
discloses "[ m ]echanisms of autoimmunity are more complicated than a
simple Th 1-Th2 dichotomy would suggest ... [and the] potential for
obtaining results different from those predicted from experiments in animals
or in vitro is great" does not overcome the other record evidence that
repeatedly teaches a connection between psoriasis and a Th 1 profile. (FF 4-
9.)
We are similarly unpersuaded that Appellants' quotations from
Griffiths show error in the Examiner's prima facie case. (Br. 4.) For
example, Appellants quote Griffiths as follows: "putative autoimmune status
is a developing concept and one that needs further clarification . . . . Most
likely, psoriasis is an autoimmune disease, of as yet unknown precipitating
antigens, set amidst a background of a critical permissive genetic
constitution .... " (Id.) The ellipted content, however, teaches that "[t]he
exact combinations of cytokines or growth factors necessary for subsequent
T-cell-driven keratinocyte proliferation are still uncertain but are consistent
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with a Th1 profile in which interferon-y is a vital component." (FF 6
(emphasis added); Ans. 15.) Elsewhere, Griffiths repeatedly connects
psoriasis to a Th 1 profile, and even teaches that "suppressing or normalizing
the Th1 profile of psoriasis" may result in effective treatment. (FF 6.)
Although portions of Griffiths reflect some uncertainty in the art, the
expectation of success needed to show obviousness need only be reasonable,
not absolute. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir.
2007) ("obviousness cannot be avoided simply by a showing of some degree
of unpredictability in the art so long as there was a reasonable probability of
success.") On balance, Griffiths and the other art of record provide
teachings sufficient to have provided the skilled person with a reasonable
expectation of success.
Finally, we have considered, but find unpersuasive, Appellants'
arguments concerning Vollmer. On the record before us, Vollmer stands in
the clear minority. The teachings of at least de Jong, Asadulla, Griffiths,
Rocken, Uyemura, and Nickoloff are consistent with psoriasis being a Th 1-
mediated disease. (FF 4-9.) We also recognize the Examiner's findings
concerning weaknesses with Vollmer's experiments compared to the
experiments described in, for example, Uyemura. (Ans. 9-12.) Appellants
have not sufficiently rebutted these findings. Medichem, S.A. v. Rolabo,
S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006) ("Where the prior art contains
apparently conflicting teachings (i.e., where some references teach the
combination and others teaching away from it) each reference must be
considered for its power to suggest solutions to an artisan of ordinary skill ..
. consider[ing] the degree to which one reference might accurately discredit
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another.") (internal quotation marks omitted). Here, the preponderance of
the evidence favors the Examiner.
In sum, based on the preponderance of the evidence of record, the
skilled artisan at the time of invention would have had a reasonable belief
that psoriasis was a Thl-mediated disease. We thus agree the skilled artisan
would have predictably treated psoriasis with nonmitogenic anti-CD3
antibodies, and done so with a reasonable expectation of success.
Conclusion of Law
We conclude the Examiner established each of Rejections I-III by a
preponderance of the evidence.
SUMMARY
We affirm the rejection of claims 16-25 under 35 U.S.C. § 103(a)
over Smith, de Jong, Asadullah, Griffiths, Rocken, Chatenoud, Chatenoud
II, Uyemura, and Nickoloff.
We affirm the rejection of claims 16-19 and 23-25 under 35 U.S.C.
§ 103(a) over Hughes, de Jong, Asadullah, Griffiths, Rocken, Chatenoud,
Chatenoud II, Uyemura, and Nickoloff.
We affirm the rejection of claims 20-22 under 35 U.S.C. § 103(a)
over Hughes, de Jong, Asadullah, Griffiths, Rocken, Chatenoud, Chatenoud
II, Uyemura, Nickoloff, and Alegre.
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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. § l.136(a).
AFFIRMED
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