Ex Parte Tsuruta

Patent Trial and Appeal Board

Jan 9, 2017

12064677 (P.T.A.B. Jan. 9, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/064,677 02/25/2008 Hideo Tsuruta SRII-328 (P6341-2) 2040
23379 7590 01/11/2017
RICHARD ARON OSMAN
530 Lawrence Expy # 332
Sunnyvale, CA 94085
EXAMINER
FINN, MEGHAN R
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
01/11/2017 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):
RICHARD @ SCI-TECH.COM
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HIDEO TSURUTA
Appeal 2015-006879
Application 12/064,677
Technology Center 1600
Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35U.S.C. § 134 involving claims to a method
for treatment of systemic hypertension. The Examiner rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse.
Statement of the Case
Background
“Hypertension is classified into two types: essential hypertension,
which cannot be attributed to any particular cause, and secondary
hypertension, resulting from an apparent cause” (Spec. 12). “Pulmonary
hypertension is a disease in which it is difficult for blood to pass through
narrowed peripheral arteriolar lumens of blood vessels carrying blood from
1 Appellant identifies the Real Party in Interest as SRI INTERNATIONAL
(see App. Br. 1).
Appeal 2015-006879
Application 12/064,677
the heart to the lungs (i.e., pulmonary arteries), resulting in an increase in
blood pressure in the pulmonary arteries” (Spec. 1 6). “Thus, pulmonary
hypertension completely differs from systemic hypertension in terms of
symptoms and definition” (id.).
The Specification teaches that generally employed “hypertension
therapeutic agents exhibit[] side effects, and may fail to be administered to
some patients. Therefore, demand has arisen for a hypertension therapeutic
agent based on a new mechanism” (Spec. 13).
The Claims
Claims 16—35 are on appeal. Claim 16 is representative and reads as
follows:
16. A method for treatment of systemic hypertension,
comprising the step of administering to a person in need thereof
an effective amount of (7a)-21-[4-[(diethylamino)methyl]-2-
methoxyphenoxy]-7-methyl-19-norpregna-l,3,5(10)-trien-3-ol,
represented by formula (1):
h3co
or a pharmaceutically acceptable salt thereof.
2
Appeal 2015-006879
Application 12/064,677
The Issue
The Examiner rejected claims 16—35 under 35 U.S.C. § 103(a) as
obvious over Tanabe,2 Thorin,3 Da Costa,4 Wassman,5 Brosnihan,6 and
Gonzalez-Perez7 (Final Act. 3—14).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that the prior art renders the claims
obvious?
Findings of Fact
1. The Specification teaches “TAS-108 [which is an abbreviation
of the compound recited in the claim] exhibits hypotensive effect
characterized by a decrease in diastolic blood pressure; and raloxifene (i.e., a
typical SERM [selective estrogen receptor modulator]) does not exhibit
2 Tanabe et al., US 6,503,896 Bl, issued Jan. 7, 2003 (“Tanabe”).
3 Thorin et al., Hyper-reactivity of cerebral arteries from ovariectomized
rats: therapeutic benefit of tamoxifen, 140 Br. J. Pharmacology 1187—
1192 (2003) (“Thorin”).
4 Da Costa et al., Effects of Hormone Replacement Therapy or Raloxifene on
Ambulatory Blood Pressure and Arterial Stiffness in Treated Hypertensive
Postmenopausal Women, 94 Am. J. Cardiology 1453—1456 (2004) (“Da
Costa”).
5 Wassman et al., Raloxifene Improves Endothelial Dysfunction in
Hypertension by Reduced Oxidative Stress and Enhanced Nitric Oxide
Production, 105 Circulation 2083—2091 (2002) (“Wassman”).
6 Brosnihan et al., Effects of droloxifene, a new selective estrogen receptor
modulator (SERM), on blood pressure and the renin-angiotensin system in
healthy post-menopausal women, 35 J. Am. College Cardiology 25 5A
(2000) (Abstract only) (“Brosnihan”).
7 Gonzalez-Perez et al., Toremifene improves vascular function in
menopause-induced rats, 17 FASEB J. Abstract 75.21 (2003) (“Gonzalez-
Perez”).
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Application 12/064,677
hypotensive effect, which indicates that, unlike the case of conventional
SERMs, TAS-108 is expected to exhibit, through daily administration, an
excellent therapeutic effect on hypertension” (Spec. 134).
2. Tanabe teaches
“Citrate Salt of 3-Hydroxy-7a-methyl-21-[2’-methoxy-4’(N ,N-
diethylamino-methy l)phenoxy]-19-norpregna-1,3,5(10)-triene ([compound]
85)” (Tanabe 76:16—32), which is TAS-108 and the same compound recited
in the claim
3. Tanabe teaches, in Example 47, “Evaluation of the Compounds
of the Invention to Inhibit Estrogen-Dependent Pulmonary Hypertensive
Disease” where the patients receive “a compound of the invention such as
compound 85” (Tanabe 87:45—55).
4. Tanabe teaches, in Example 43 that “[w]ith respect to the MCF-
7 tumor, all compounds showed a significant growth-suppressive activity.
Ten mg/kg/day of compound 85 and 25 mg/kg/day of compound 92 showed
the strongest growth inhibitory activity” (Tanabe 85:39-42).
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Application 12/064,677
5. Thorin teaches: “Tamoxifen and raloxifene are representative of
a family of molecules designated as selective estrogen receptor modulators
(SERM)” (Thorin 1187, col. 2).
6. Thorin teaches: “Tamoxifen treatment of OVX rats normalized
LVEDP [left ventricular end diastolic pressure], —dp/dt, modestly reduced
LVSP [left ventricular systolic pressure]” (Thorin 1189, col. 1).
7. Da Costa teaches that in “comparison with HRT [hormone
replacement therapy], raloxifene therapy demonstrated similar improvement
on vascular stiffness, independently of the BP [blood pressure] reduction,
although HRT promoted a more significant reduction in the average BP
compared with baseline levels” (Da Costa 1455, col. 2).
8. Wassman teaches “[s]ystolic blood pressure was similar in both
Wistar groups before treatment and was significantly reduced after treatment
with raloxifene compared with the systolic blood pressure of control
animals” (Wassman 2085, col. 1).
9. Brosnihan teaches “D [droloxifene] significantly lowered
standing systolic (140 vs. 130 [] mmHg and diastolic (75 vs. 66 mmHg) B.
P. [blood pressure]” (Brosnihan, abstract).
10. Gonzalez-Perez teaches “systolic blood pressure in menopausal
women is significantly reduced by treatment with selective estrogen receptor
modulators (SERMs)” (Gonzalez-Perez, abstract).
11. Y amamoto8 teaches:
8 Yamamoto et al., TAS-108, a Novel Oral Steroidal Antiestrogenic Agent, Is
a Pure Antagonist on Estrogen Receptor a and a Partial Agonist on
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The characteristic summaries of the unique mode of action of
TAS-108, when compared with other known antiestrogenic
agents are follows: in comparison to tamoxifen, TAS-108 is a
pure antagonist on ERa unlike tamoxifen. On ER[3, it acts as a
partial agonist similar to tamoxifen but both modes of action
are different. Tamoxifen induces no AF-2 transactivation of
ER[3, whereas TAS-108 markedly induces AF-2 transactivation
by promoting the recruitment of TIF-2, a co-activator. In the
comparison to raloxifene, a selective estrogen receptor
modulator, although raloxifene is a pure antagonist of ERa, it
acts as an agonist on D351Y mutant ERa derived from a
tamoxifen-resistant breast cancer cell line. TAS-108 acts as an
ERa antagonist even in this mutant. The antagonistic activity of
raloxifene on ER[3 is much weaker than that on ERa. This is
because its binding affinity to ER[3, is 10 times weaker than that
of ERa. On the other hand, TAS-108 binds both ERs with the
same affinity. In comparison, fulvestrant acts as a pure
antiestrogen on both ERa and ER[3, via down-regulation of ERs
and binding inhibition of ERs to DNA. This is completely
different from the mode of action of TAS-108 which modulates
the recruitment of coregulators to ERs and exhibits agonistic
properties on ER[3, in the absence of E2.
(Yamamoto 321, col. 1; citations and references omitted).
12. Yamamoto teaches some SERM “drugs have no agonistic
activity on ERs and lack the clinical benefits of tamoxifen’s agonistic
properties, such as the prevention of osteoporosis and cardiac disease” and
that “TAS-108 had high binding affinity to ERa and inhibited its
transactivation without any agonistic properties, which is in striking contrast
Estrogen Receptor f3 with Low Uterotrophic Effect, 11 Clinical Cancer Res.
315-322 (2005) (“Yamamoto”).
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Application 12/064,677
to the agonistic property of tamoxifen” (Yamamoto 320, col. 2; citations and
references omitted).
13. Yamamoto teaches the “biological function of ERJ3 is still not
well understood and controversial, and we have not had enough data to link
the agonistic action of TAS-108 and ER[3 to its beneficial effect”
(Yamamoto 321, col. 1, citations omitted).
14. Maximov9 teaches that “[cjlinical data on newer SERMs in
development indicate that these compounds may, or may not, have attributes
that represent an improvement relative to currently available SERMs”
(Maximov 150, col. 1; references omitted).
Principles of Law
O ’Farrell states that “[ojbviousness does not require absolute
predictability of success.” In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir.
1988). However, O’Farrell identifies
9 Maximov et al., The Discovery and Development of Selective Estrogen
Receptor Modulators (SERMs) for Clinical Practice, 8 Current Clinical
Pharmacology 135155 (2013) (“Maximov”).
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two kinds of error. In some cases, what would have been
“obvious to try” would have been to vary all parameters or try
each of numerous possible choices until one possibly arrived at
a successful result, where the prior art gave either no indication
of which parameters were critical or no direction as to which of
many possible choices is likely to be successful. . . In others,
what was “obvious to try” was to explore a new technology or
general approach that seemed to be a promising field of
experimentation, where the prior art gave only general guidance
as to the particular form of the claimed invention or how to
achieve it.
(Id.)
Analysis
The Examiner finds:
4 different selective estrogen receptor modulating
compounds (SERMs) have been identified as lowering blood
pressure in both hypertensive and postmenopausal women.
It would have been obvious to use the TAS-108 of Tanabe to
treat a postmenopausal woman with breast cancer (already
taught by Tanabe) who was suffering from systemic
hypertension.
(Ans. 4).
Appellant contends that “SERMS are structurally and functionally
diverse molecules, wherein functionality is demonstrably not extrapolatable
across diverse structures (see, e.g. Maximov et al. 2013, Curr Clin
Pharmacol 8, 135-155 and Osborne et al. 2000, J Clin Oncol 18, 31372-
3186), and TAS-108 and Raloxifen (and Tamoxifen, for that matter) are
about as diverse as you can get, chemically” (App. Br. 6).
We note that independent claims 16 and 26 are not drawn to the TAS-
108 compound, but rather to a method of administering TAS-108 for
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treatment of systemic hypertension. Therefore, consistent with the
Examiner’s reasoning that TAS-108 is a SERM and that certain specific
SERMs treat hypertension (see Ans. 4; FF 6—10), in order for the claims to
be obvious, there must be a reasonable expectation of success in treating
systemic hypertension with TAS-108.
While this is a close case, we find that Appellant has the better
position. Tanabe proposes, but does not demonstrate, the efficacy of TAS-
108 on pulmonary hypertension (FF 3) and provides no teaching suggesting
treatment of systemic hypertension with TAS-108. Tanabe shows that TAS-
108 shares the antitumor activity of two SERMs, tamoxifen and raloxifene
(FF 4), but Tanabe provides no evidence showing that TAS-108 is
equivalent in all respects with other SERMs. Moreover, while Thorin, Da
Costa, Wassman, Brosnihan, and Gonzalez-Perez show that certain SERMs
reduce hypertension (FF 6—10), none of these references demonstrate that
TAS-108 is functionally equivalent to these SERMs, or that it shares the
same mechanism of action regarding interactions with estrogen receptors
a and [3, or shares substantial common structure with the other SERMS.
In contrast, Yamamoto, a prior art reference, teaches TAS-108 has
unique modes of action relative to other SERMS including different
interactions (e.g., receptor binding and pharmacological activity) with
estrogen receptors (FF 11). This evidence of nonequivalence is buttressed
by Maximov’s recognition that different SERMs may have different
attributes (FF 14).
Even the portion of Yamamoto identified by the Examiner (see Ans.
8) demonstrates the nonequivalence of tamoxifen and TAS-108. Yamamoto
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teaches tamoxifen’s clinical benefit on cardiac disease operates through
agonistic properties on ER, but that TAS-108 lacked such agonistic
properties towards ERa, even though it bound to it (FF 12). Thus, the
ordinary artisan would not have reasonably expected that TAS-108 would
necessarily share the favorable cardiac properties of tamoxifen because it
lacked the agonistic properties of tamoxifen.
We recognize that Yamamoto makes the general statement that TAS-
108 has agonistic benefits for cardiac disease (Yamamoto 321, col. 2), but
Yamamoto also states that the “biological function of ERp is still not well
understood and controversial, and we have not had enough data to link the
agonistic action of TAS-108 and ERp to its beneficial effect” (FF 13).
We conclude that the instant situation falls closest to an “obvious to
try” situation where TAS-108 is one of large group of agents taught by
Tanabe for a variety of different conditions, none of which was systemic
hypertension, and that the prior art gives no indication regarding that TAS-
108 would likely be successful in treating systemic hypertension, nor was
there specific guidance that compounds with the ER interacting profile of
TAS-108 would be reasonably expected to predictably treat systemic
hypertension.
We therefore agree with Appellant that “TAS-108 is a steroid and
completely unrelated to any nonsteroidal SERM - both structurally and
functionally” and that “even if there was a common SERM mechanism of
action across steroids and nonsteroids, there is simply nothing of record to
suggest that such a hypothetical common function is known to be the
mechanism to treat systemic hypertension” (Reply Br. 3).
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Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that the prior art renders the claims obvious.
SUMMARY
In summary, we reverse the rejection of claims 16—35 under 35 U.S.C.
§ 103(a) as obvious over Tanabe, Thorin, Da Costa, Wassman, Brosnihan,
and Gonzalez-Perez.
REVERSED
11