Ex Parte Guglielmotti et al

Patent Trial and Appeal Board

Nov 29, 2017

13382450 (P.T.A.B. Nov. 29, 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.
13/382,450 04/26/2012 Angelo Guglielmotti 388791US99PCT 5714
22850 7590 12/01/2017
OBLON, MCCLELLAND, MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA, VA 22314
EXAMINER
CRUZ, KATHRIEN ANN
ART UNIT PAPER NUMBER
1621
NOTIFICATION DATE DELIVERY MODE
12/01/2017 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
following e-mail address(es):
patentdocket @ oblon. com
oblonpat @ oblon. com
tfarrell@oblon.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ROBERTA PETROSEMOLO, ENRICA BIONDI,
and IACOPO BIONDI
Appeal 2016-002285
Application 13/3 82,4501
Technology Center 1600
Before JOHN G. NEW, TIMOTHY G. MAJORS, and DAVID COTTA,
Administrative Patent Judges.
COTTA, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for treating an inflammatory disease caused by the expression of cytokine
subunit p40. The Examiner rejected the claims on appeal as obvious under
35 U.S.C. § 103(a).
We affirm.
1 According to Appellants, the real party in interest is Aziende Chim. Riun.
Ang. Franc. A.C.R.A.F., S.p.A. App. Br. 1.
Appeal 2016-002285
Application 13/382,450
STATEMENT OF THE CASE
The Specification discloses that compounds “capable of interfering
with TNF such as etanercept, infliximab and adalimumab have been
developed and clinically tested for the treatment of Crohn’s disease,
rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing
spondylitis.” Spec. 3. The Specification reports, however, that “the use of
compounds capable of interfering with TNF . . . has been quite limited by
safety issues” and that “clinical trials and clinical practice demonstrated that
the use of anti-TNF agents is often associated with the appearance of the
typical immunosuppressive sequaela [sic] such as infections, malignancy, or
autoimmune disorders.” Id.
The Specification discloses that “[pjsoriasis is a chronic inflammatory
skin disease that affects 3% of the world’s population” {id. at 4), and that
“recently, several scientific works indicated that cytokine subunit p40 can
play a fundamental role in psoriasis pathogenesis.” Id. at 3. The
Specification asserts that “the Applicant has surprisingly found that
benzydamine is able to inhibit the expression and overexpression of the
cytokine subunit p40,” that “benzydamine is active on cytokine subunit p40
at lower concentrations with respect to those previously reported for its
activity on TNF,” and that “benzydamine can be used for the treatment of
inflammatory diseases caused by an expression or overexpression of the
cytokine subunit p40, such as, for example . . . psoriasis.” Id. at 6.
Claims 6-11, 21, 25, and 26 are on appeal. Claim 6 is illustrative and
reads as follows:
6. A method for treating an inflammatory disease caused by
the expression of cytokine subunit p40, the method comprising:
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Application 13/382,450
administering a therapeutically effective amount of
benzydamine or a physiologically acceptable acid addition salt
of benzydamine to a patient in need thereof.
App. Br. 13.
The Examiner rejected claims 6-11, 21, 25, and 26 under 35
U.S.C. § 103(a) as obvious over the combination of Sironi,2 Schon,3
and Lee.4
FINDINGS OF FACT
1. Sironi discloses:
N,N-dimethyl-3-[( 1 -benzyl- lH-indazol-3-yl)ossi]-1 -
propanamine (benzydamine) is an anti-inflammatory drug
devoid of effects on arachidonate metabolism. Its mechanism of
action is not yet completely defined. It is presently in clinical
use as a topical agent. This work was performed to characterize
the effect of benzydamine on cytokine production, using human
and mouse cells in vitro and extending the investigation to in
vivo toxic shock in mice. Benzydamine inhibited production of
TNF-a, and to a lesser extent IL-|3, but not of IL-6 in vitro and
in vivo. It also protected mice against LPS lethality. Thus
benzydamine, long in therapeutic use, can now be considered in
the perspective of a novel cytokine-suppressive anti­
inflammatory drug.
Sironi 710 (footnote omitted).
2 Sironi et al., Inhibition of Inflammatory Cytokine Production and
Protection Against Endotoxin Toxicity by Benzydamine, 8(9) Cytokine,
710-716 (1996) (“Sironi”).
3 Schon et al., Psoriasis, 352(18) N. Engl. J. Med. 1899-1912 (2005)
(“Schon”).
4 Lee et al., Increased Expression of Interleukin 23 pl9 and p40 in Lesional
Skin of Patients with Psoriasis Vulgaris, 199(1) J. Exp. Med., 125-130
(2004) (“Lee”).
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Application 13/382,450
2. Schon discloses that “[pjsoriasis [is] a common inflammatory
skin disorder.” Schon 1899.
3. Schon discloses:
Five general therapeutic principles target the key pathogenic
mechanisms of psoriasis. . . . The fourth principle is functional
inhibition of key inflammatory cytokines (Panel. D). Perhaps
the most important example is tumor necrosis factor a (TNF-a),
the functions of which are targeted by several biologic agents,
the monoclonal antibodies infliximab and adalimumab, and the
fusion proteins etanercept and onercept.
Id. at 1909.
4. Schon discloses: “A key cytokine in psoriasis (and in other
inflammatory diseases) is TNF-a, which can be functionally inhibited by the
chimeric antibody infliximab or by the recombinant human TNF-receptor
fusion protein etanercept.” Id. at 1910.
5. The Specification states:
Benzydamine has been widely used in practice of human
treatment as hydrochloride salt. By the systemic route it is
mainly used as an antiphlogistic and analgesic. Topically it is
however mainly used for those diseases which involve local
inflammation such as for example myalgia, tendinitis,
vulvovaginitis, gingivitis, stomatitis, mucositis of the oral
cavity and so forth. Moreover benzydamine salicylate has been
used in rheumatic disorders.
Spec. 1 (“Background”).
6. The Specification states:
Given the lack of reliable experimental animal models for
psoriasis (Lowes MA et al. Nature 2007; 445:866-73) and
taking into account the long lasting experience with
benzydamine in human, its low systemic exposure after topical
administration and the excellent safety profile, benzydamine
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Application 13/382,450
was tested as a 5% cream (corresponding to the formulation of
the following table 8) in a small group of patients affected by
psoriasis.
Id. at 13-14.
7. The Specification discloses that the “use of benzydamine for
preparing a medicament for the treatment of pathological conditions caused
by TNF, a non-glycosylated polypeptide, also known as alpha TNF or
cachectin” was known. Id. at 2.
8. Table 2 of the Specification is reproduced below.
TABLE 2
BsnxyxLif'Kf!* % inhibition
InfcS
100 89
m 9?
10 44
3 24
23
0 0
Spec. 12. Table 2 reports results obtained from testing the effect of
benzydamine on p40 production in vitro based on stimulation of human
peripheral blood mononuclear cells. Id. Table 2 is included in Example 2 of
the Specification. Id.
9. Table 3 of the Specification is reproduced below.
TABLE 3
Benzydamine
EmMI
% inhibition
100 70
30 44
10 22
3 12
8
0 7
Spec. 13. Table 3 reports results obtained from testing the effect of
benzydamine on TNF production in vitro based on stimulation of human
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Application 13/382,450
peripheral blood mononuclear cells. Id. Table 3 is included in Example 3 of
the Specification. Id.
10. The Wikipedia entry on etanercept (Enbrel) referenced in
paragraph 12 of the Guglielmotti Declaration states that etanercept was
“released for commercial use in late 1998” and also states that “[sjales were
$3.3 billion in 2010.” http://en.wikipedia.org/wiki/Etanercept.
11. The Wikipedia entry on infliximab (Remicade) referenced in
paragraph 13 of the Guglielmotti Declaration states that “[ijnfliximab was
approved by the U.S. Food and Drug Administration (FDA) for the
treatment of psoriasis, Crohn’s disease, ankylosing spondylitis, psoriatic
arthritis, rheumatoid arthritis, and ulcerative colitis. Infliximab won its
initial approval by the FDA for the treatment of Crohn’s disease in August
1998.” http: //en.wikipedia. org/wiki/Infliximab.
12. The Wikipedia entry on adalimumab (Humira) referenced in
paragraph 13 of the Guglielmotti Declaration states that adalimumab was
“approved by the U.S. Food and Drug Administration (FDA) for treatment
of rheumatoid arthritis” in 2002 and “[ejxceeded $1 billion in annual sales
for the first time” in 2005. It further states: “In 2009, HUMIRA had over $5
billion in annual sales, whilst in 2012 the drug reached $4.3 billion of sales
in the US alone, achieving $9.3 billion in worldwide sales for that year.”
http://en.wikipedia.org/wiki/Adalimumab (footnotes omitted).
OBVIOUSNESS OVER SIRONI, SCHON, AND FEE
Appellants argue all of the claims together. We designate claim 6 as
representative.
In rejecting claim 6 as obvious, the Examiner found that Sironi
disclosed that “N, N-dimethyl-3-[(l-benzyl-lH-indazol-3-yl)ossi]-l-
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Application 13/382,450
propanamine (benzydamine) is an anti-inflammatory drug” that “inhibits
production of inflammatory cytokines by human and murine mononuclear
phagocytes exposed to various inducers.” Non-Final Act.5 6-7. The
inhibitory effect “was preferential, in that TNF-a and to a lesser extent IL-lb
were consistently inhibited.” Id. at 7. The Examiner further found that
Sironi disclosed that “the anti-inflammatory activity of benzydamine has
long been known and this agent in currently used topically.” Id. The
Examiner acknowledged, however, that the Sironi did not disclose the
treatment of psoriasis.
The Examiner found that Schon disclosed that “psoriasis [was] a
common inflammatory skin disorder” and that “numerous studies have
identified tumor necrosis factor (TNF-a) as a particularly relevant cytokine
regulating this complex inflammatory cascade.” Id. Based on the teachings
of Sironi and Schon, the Examiner concluded that it would have been
obvious to administer benzydamine for treatment of psoriasis because it was
“known in the art at the time of the invention . . . that benzydamine is useful
in the inhibition of TNF-a and inflammatory cytokines and that psoriasis is
caused by the over-production of TNF and cytokines.” Id. at 7-8.6
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Non-Final Act. 3-10; Ans. 2-15) and
agree that claim 6 would have been obvious over Sironi, Schon, and Lee.
We address Appellants’ arguments below.
5 Office Action mailed November 6, 2014 (“Non-Final Act.”).
6 The Examiner also relied upon Lee for teachings related to p40. Non-Final
Act. 7-8.
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Appellants argue that TNF-a inhibitors, including etanercept,
infliximab, adalimumab, were known to have severe adverse effects. App.
Br. 3-7. Appellants cite to the Specification and the Guglielmotti
Declaration7 as teaching that “the use of compounds capable of interfering
with TNF has been quite limited by safety issues and that the use of anti-
TNF agents was often associated with the appearance of the typical
immunosuppressive sequaela [sic] such as infections, malignancy, or
autoimmune disorders.” Id. at 5. In addition, Appellants point to a possible
association between TNF blockers and the development of lymphoma and
other cancers in children and young adults (App. Br. 5; Guglielmotti Decl. ^
11), a black box warning on the TNF blocker etanercept (App. Br. 6;
Guglielmotti Decl. ^ 12), and the knowledge of “adverse effects after
administration of Remicade (infliximab) and Humira (adalimumab).” App.
Br. 6; Guglielmotti Decl. ^] 13. In view of this evidence, Appellants contend
that the skilled artisan “would have expected serious negative side effects to
occur by administering a TNF inhibitor ... for the treatment of a disorder
involving TNF.” App. Br. 6; Guglielmotti Decl. ^ 14. We are not
persuaded.
While we recognize that other TNF-a inhibitors may have severe
adverse effects, Appellants have not provided any evidence of severe
adverse effects specific to benzydamine. In fact, Sironi states that
benzydamine has been “long in therapeutic use” (FF1) and the Specification
states that benzydamine is “widely used in practice of human treatment.”
FF5. In addition, in explaining why benzymadine was tested on patients in
7 Declaration of Dr. Angelo Guglielmotti under 37 C.F.R. § 1.132, dated
July 18, 2014 (“Guglielmotti Deck”).
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Application 13/382,450
the manner described in connection with Example 4, the Specification
references “taking into account the long lasting experience with
benzydamine in human, its low systemic exposure after topical
administration and the excellent safety profile.” FF6. This suggests that the
skilled artisan would not have been discouraged from using benzydamine by
the adverse effects connected to other TNF-a inhibitors.
Moreover, while the TNF-a inhibitors identified by Appellants are
described as having the potential for severe side effects, they are all FDA-
approved pharmaceuticals. FF10-FF12. Indeed, the Wikipedia entries
provided by Appellants for etanercept and adalimumab report annual sales in
the billions of dollars See, FF10 & FF12. This further suggests that the
skilled artisan would not have been discouraged from pursuing treatments
using benzydamine.
Appellants argue that results disclosed in Example 4 of the
Specification are surprising because they were achieved using topically
administered benzydamine while infliximab and etanercept are
“administered by subcutaneous injection.” App. Br. 4. We do not find this
to be persuasive of nonobviousness because Sironi teaches that benzydamine
is “presently in clinical use as a topical agent.” FF1.
Appellants argue that the Examiner “fails to appreciate the surprising
and unexpected finding by the Inventors of the present application that
benzydamine is acting by inhibiting p40 rather than acting by inhibiting
TNF.” App. Br. 8 (emphasis omitted). We are not persuaded.
As an initial matter, the evidence does not establish that benzydamine
acts on p40 to the exclusion of TNF-a. To the contrary, Example 3 of the
Specification suggests that benzydamine inhibits TNF-a even at low
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Application 13/382,450
concentrations. FF9; see also FF1 and FF8 (showing inhibition of p40).
Moreover, as discussed above, we agree with the Examiner that it would
have been obvious to administer benzydamine for the treatment of psoriasis.
See FF1-4. That the motivation posited by the Examiner for treating
psoriasis using benzydamine derives from expectations with respect to
benzydamine’s inhibitory effect on TNF-a rather than p40 does render the
claimed method nonobvious. Alcon Research, Ltd. v. Apotex Inc., 687 F.3d
1362, 1368 (Fed. Cir. 2012) (“We have repeatedly held that the motivation
to modify a prior art reference to arrive at the claimed invention need not be
the same motivation that the patentee had.”): In re Dillon, 919 F.2d 688, 693
(Fed. Cir. 1990) (“[I]t is not necessary in order to establish aprima
facie case of obviousness that both a structural similarity between a claimed
and prior art compound (or a key component of a composition) he shown
and that there be a suggestion in or expectation from the prior art: that the
claimed compound or composi tion will have the same or a similar utility as
one newly discovered by applicant.”).
To the extent that inhibition of p4Q when benzydamine is
administered to treat psoriasis is considered to be a newly discovered
mechanism of action,8 we note that a newly discovered result or property of
an existing (or obvious) method of use does not confer patentability. See
Abbott Labs. v. Baxter Pharm. Prods., 471 F.3d 1363, 1368-69 (Fed. Cir.
8 Lee discloses that IL-23 is a cytokine “composed of two subunits: a unique
pl9 subunit and a p40 subunit shared with IL-12” (Lee Abstract) and teaches
that “IL-23 antagonists might be the most appropriate treatment for
inflammatory skin diseases like psoriasis.” Id. at 130. Sironi teaches that
benzydamine is a “cytokine-suppressive anti-inflammatory drug.” Sironi
710.
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Application 13/382,450
2006); In re Cruciferous Sprout Litig., 301 F.3d 1343, 1350-51 & n.4 (Fed.
Cir. 2002); Bristol-Myers Squibb Co. v. Ben Venue Labs., 246 F.3d 1368,
1376 (Fed. Cir. 2001).
Appellants argue that “the present inventors found that benzydamine
inhibits p40 at a lower dosage than that necessary to inhibit TNF.” App. Br.
8. Appellants contend that “benzydamine was able to significantly inhibit
the anti-CD3 induced production of p40 with an IC50 of 10.1 pM while it
was able to inhibit the anti-CD3 induced production of TNF with an IC50 of
43.1 pM that is about 4 fold higher than that obtained with p40.” App. Br. 8
(citing Guglielmotti Decl. ^ 21). We are not persuaded.
The evidence Appellants rely upon as establishing that benzydamine
inhibits p40 at a lower dosage than is necessary to inhibit TNF is ultimately
based on Examples 2 and 3 of the Specification. Examples 2 and 3 provide
in vitro testing data on stimulated human peripheral blood mononuclear
cells. Spec. 12-13; see FF8 & FF9. As Appellants themselves recognize in
connection with the in vitro data provided in Sironi, in vitro data does not
establish effective doses for treating a disease in vivo. Reply Br. 2 (“The
use of a concentration of benzydamine ranging from 0 to 50 pMin in an in
vitro test has nothing to do with a dosage of benzydamine expressed in terms
of jig/kg or mg/kg in an in vivo test.”). As the claims at issue are directed to
in vivo treatment of disease, Appellants’ evidence regarding inhibition at
lower concentrations in vitro is not persuasive.
In their Reply Brief, Appellants argue that the Examiner incorrectly
identified the dosage range as being 50 pg/kg to 40 mg/kg. Id. While we
are inclined to agree with Appellants that the Examiner misidentified the
dosage range, we find that this issue was waived because Appellants first
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Application 13/382,450
raised it in the Reply Brief, depriving us of the benefit of the Examiner’s
response. See Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010)
(informative) (“[T]he reply brief [is not] an opportunity to make arguments
that could have been made in the principal brief on appeal to rebut the
Examiner’s rejections, but were not.”). Moreover, we note that even in the
Reply Brief, Appellants have not tied this purported error to any particular
claim or claim limitation.
Accordingly, we affirm the Examiner’s rejection of claim 6 as obvious
over the combination of Sironi, Schon, and Lee. Because they were not
argued separately, claims 7-11, 21, 25, and 26 fall with claim 6.
SUMMARY
For the reasons set forth herein, and those set forth in the Examiner’s
Answer and Non-Final Office Action, we affirm the Examiner’s rejection of
claims 6-11, 21, 25, and 26 as obvious over the combination of Sironi,
Schon, and Lee.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv). See
37 C.F.R. § 41.50(f).
AFFIRMED
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