Ex Parte Guo

Board of Patent Appeals and Interferences

Oct 31, 2011

12101444 (B.P.A.I. Oct. 31, 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.
12/101,444 04/11/2008 ZhongMao Guo 9383-3 8230
20792 7590 10/31/2011
MYERS BIGEL SIBLEY & SAJOVEC
PO BOX 37428
RALEIGH, NC 27627
EXAMINER
RAO, SAVITHA M
ART UNIT PAPER NUMBER
1629
MAIL DATE DELIVERY MODE
10/31/2011 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 ZHONGMAO GUO
__________

Appeal 2011-001659
Application 12/101,444
Technology Center 1600
__________

Before DONALD E. ADAMS, LORA M. GREEN, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner‟s rejection of claims 18-25. We have jurisdiction under 35 U.S.C.
§ 6(b).
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STATEMENT OF THE CASE
Claim 18 is the only independent claim on appeal, and reads as
follows:
18. A method of treating atherosclerosis or hyperlipidemia in a human
subject in need thereof, comprising orally administering said subject 2-
aminopurine or a pharmaceutically acceptable salt thereof in an effective
amount, wherein said human subject has an ApoE2 or ApoE4 isoform.

The following ground of rejection is before us for review:
Claims 18-25 stand rejected under 35 U.S.C. § 103(a) as being
rendered obvious by the combination of Hosoi,
1
Beltowski,
2
Gray,
3
and
Davignon.
4

We reverse.
ISSUE
Does a preponderance of the evidence of record support the
Examiner‟s conclusion that the combination of Hosoi, Beltowski, Gray, and
Davignon renders obvious the method of treating atherosclerosis or
hyperlipidemia in a human subject of claim 18?

1
Hosoi et al., 2-Aminopurine inhibits leptin receptor signal transduction,
553 EUR. JOUR. OF PHARMACOLOGY 61-66 (2006).
2
Jerzy Beltowski, Leptin and atherosclerosis, 189 ATHEROSCLEROSIS 47-60
(2006).
3
Gray et al., US 6,255,485 B1, July 3, 2001.
4
Davignon et al., Apolipoprotein E and atherosclerosis: insight from animal
and human studies, 286 CLINICA CHIMICA ACTA 115-143 (1999).
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FINDINGS OF FACT
FF1. The Examiner‟s statement of the rejection may be found at pages 4-9
of the Answer.
FF2. Hosoi teaches that 2-aminopurine (2-AP) “inhibited the leptin-induced
phosphorylation of signal transducer and activator of transcription 3
(STAT3), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal
kinase (JNK) in HEK293 cells stably transfected with the Ob-Rb leptin
receptor” (Hosoi, Abstract).
FF3. Hosoi concludes that “2-AP might be useful as a drug for leptin-
mediated cancer therapy” (id. at p. 65, second column).
FF4. Hosoi teaches further that the concentration of 2-AP required to
interfere with leptin signaling is high for therapeutic use, and thus 2-AP may
be useful as a lead compound (See Hosoi, p. 65, paragraph bridging the
columns).
FF5. The Examiner notes that “Hosoi does not teach the administration of
2-aminopurine for the treatment of atherosclerosis in a mammalian subject”
(Ans. 6).
FF6. The Examiner relies on Beltowski for teaching that “increase in
vascular levels of leptin (hyperleptinemia) may play an important role in
obesity-associated diseases including atherosclerosis and that leptin exerts
many potentially atherogenic effects such as induction of endothelial
dysfunction stimulation of inflammatory vascular smooth muscle cells
(abstract)” (id. at. 6).
FF7. The Examiner also finds that “Beltowski suggests that leptin may be
target[ed] by some currently used therapeutic interventions in atherosclerosis
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such as fibrates, statins and thiazolidinediones which decrease leptin
production (page 56, right col. 1
st
paragraph)” (id.).
FF8. The Examiner thus concludes that “Beltowski provides motivation to
an ordinarily skilled artisan to use 2-aminopurine in the treatment of patients
with atherosclerosis” (id.).
FF9. Beltowski teaches that “[p]lasma leptin concentration is proportional
to body adiposity and is markedly increased in obese individuals,” and that
“hyperleptinemia may play an important role in obesity-associated
cardiovascular diseases including atherosclerosis” (Beltowski, Abstract).
Thus, according to Beltowski, “[i]nhibition of leptin signaling may be a
promising strategy to slow the progression of atherosclerosis in
hyperleptinemic obese subjects” (id.).
FF10. Beltowski presents two possible explanations for the relationship
between leptin and atherosclerosis in Figure 1, reproduced below:

As shown in the left, obesity may be associated with hyperleptinemia due to
increased amounts of adipose tissue, enhancing the proatherogenic effects of
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leptin. As shown on the right, obesity is associated with leptin resistance at
both hypothalamic and peripheral levels, and the resistance to beneficial
effects of leptin contribute to atherogenesis (id. at p. 49, Figure 1, legend).
FF11. According to Beltowski, the “correlation between elevated leptin and
atherosclerosis observed in humans does not allow differentiating between
the two possibilities” (id. at 49, first column).
FF12. Beltowski teaches further:
Several studies have demonstrated the inverse
relationship between leptin and HDL-cholesterol and/or
apolipoprotein AI in humans. Ob/ob mice have high HDL, and
a series of elegant studies has demonstrated that leptin promotes
hepatic HDL clearance by upregulating scavenger receptor type
Bl, and decreases plasma HDL level in these mice. Thus, leptin
may impair cholesterol removal from peripheral tissues by
lowering HDL.

((Id. at 51, first column (references omitted).)
FF13. Beltowski also teaches that “leptin might contribute to
proinflammatory state associated with obesity” (id. at 51, first column).
FF14. Beltowski also notes that data in apolipoprotein E knockout mice
“suggest that alterations of leptin signaling accelerate atherosclerosis if
superimposed on specific genetic backgrounds” (id. at 54-55 ).
FF15. Beltowski concludes:
As can be concluded from the data presented above,
leptin exerts many potentially proatherogenic effects both in
vitro and in vivo. Several clinical studies including some
prospective ones suggest that high plasma leptin is associated
with the development of atherosclerosis and its complications.
However, the question if hyperleptinemia is involved in the
pathogenesis of atherosclerosis in obese subjects is still
unresolved since all the evidence currently available is only
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indirect. The findings that ob/ob and db/db mice are protected
from atherosclerosis indicate that physiological level of leptin is
necessary for its development. However, this does not
necessarily indicate that supraphysiologically elevated leptin
further augments atherogenesis, especially if one considers that
obesity induces resistance to some proatherosclerotic effects of
leptin. In addition, arterial injury models used in experimental
studies resemble but not exactly reproduce human
atherosclerotic lesions. Studies in which exogenous leptin is
chronically administered to experimental animals suffer from
the limitation of intact leptin signaling, although chronic
hyperleptinemia may also per se induce leptin resistance. The
association between leptin and atherosclerosis in humans does
not necessarily prove the causal relationship since leptin might
simply correlate with the other proatherogenic factor not
examined in a given study or even still not recognized such as
other adipokine(s). Finally, few studies suggesting protective
effects of leptin, and possibly atherogenic effect of leptin
resistance (Fig. 1) should not be completely neglected.

(Id. at 56, first column (references omitted).)
FF16. According to the Examiner:
Since 2-aminopurine as taught by Hosoi has an effect to
decrease peripheral leptin and the other known anti-
hyperlipedimic agents also possess the same mechanism as
taught by Beltowski, it would have been obvious to an
ordinarily skilled artisan to combine the teachings of Hosoi and
Beltowski to develop a method of treating atherosclerosis with
2-aminopurine. Beltowski additionally teaches the acceleration
of atherosclerosis if leptin depletion is superimposed on
specific genetic background such as patients with impaired
apoE isoforms. As such developing a method of treating
patients with a deficient apoE isoforms with 2-aminopurine
which acts by decreasing leptin would have been obvious to an
ordinarily skilled artisan. It is the examiner‟s position that an
ordinarily skilled artisan will utilize 2-aminopurine to treat
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atherosclerosis in any patient who is manifesting the symptoms
and signs of atherosclerosis irrespective of its etiology.

(Ans. 9.)

PRINCIPLES OF LAW
A rejection for obviousness must include “articulated reasoning with
some rational underpinning to support the legal conclusion.” KSR Int’l Co.
v. Teleflex Inc., 550 U.S. 398, 418 (2007), quoting In re Kahn, 441 F.3d 977,
988 (Fed. Cir. 2006). The proper question to ask is whether a person of
ordinary skill in the art, facing the wide range of needs created by
developments in the field of endeavor, would have seen a benefit to
combining the prior art teachings. KSR, 550 U.S. at 424; see also In re
Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004) (the desirability of the
combination may arise from nature of the problem, teachings of references,
or the ordinary knowledge of those skilled in the art).
[A] combination of familiar elements according to known
methods is likely to be obvious when it does no more than yield
predictable results. . . . [I]f a technique has been used to
improve one device, and a person of ordinary skill in the art
would recognize that it would improve similar devices in the
same way, using the technique is obvious unless its actual
application is beyond that person‟s skill.

KSR, 550 U.S. at 401.

ANALYSIS
Appellants argue that the combination as set forth by the Examiner
does not provide a reasonable expectation of success that one could treat
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atherosclerosis or hyperlipidemia using 2-aminopurine (App. Br. 8).
Specifically, as to Beltowski, Appellants argue that Beltowski teaches “that
the relationship between leptin and atherosclerosis is highly complex; one
main theory stating that leptin activity may promote atherogenesis, the other
that it may inhibit it” (id. at 9). Appellants assert that given that complexity,
the effect of targeting leptin in the treatment of atherosclerosis would have
been unpredictable (id. at 9-10). Appellants assert that “at best, Beltowski
merely suggests the exploration of a field of experimentation with respect to
leptin inhibition/activation and atherosclerosis, and that this is insufficient as
a matter of law to support a rejection under 35 U.S.C. § 103” (id. at 10).
We agree with Appellants. The Court of Appeals for the Federal
Circuit set forth In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988), two
situations in which an “obvious to try” rationale was usually improperly
applied. The first situation of “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.” (Id.) The second
situation of “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. See In re Kubin, 561 F.3d
1351, 1358-60 (noting that the rationale in O’Farrell was “affirmed [in] the
logical inverse” in KSR, 550 U.S. at 417, in the Statement that “§103 likely
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bars its patentability” unless “the improvement is more than the predictable
use of prior art elements according to their established functions.”).
Based on the above framework, we conclude that, at best, it may have
been obvious to try and use 2-aminopurine for the treatment of
atherosclerosis or hyperlipidemia in a human subject. Hosoi teaches that 2-
AP interferes with leptin signal transduction. Beltowski, while teaching that
inhibition of leptin signaling may be a promising strategy to slow the
progression of atherosclerosis in hyperleptinemic obese subjects, teaches
that leptin may be involved in the progression of atherosclerosis in several
ways, and that the correlation between elevated leptin and atherosclerosis
does not differentiate between the two possibilities. Beltowski also notes
that association between leptin and atherosclerosis in humans does not
necessarily prove a causal relationship. Thus, we conclude that this situation
is analogous to the second situation discussed by the O’Farrell court, and
there would not have been a reasonable expectation of success of using 2-AP
in the treatment of atherosclerosis or hyperlipidemia in a human subject.
See, e.g., Kubin, 561 F.3d at 1361.

CONCLUSION OF LAW
We conclude that a preponderance of the evidence of record does not
support the Examiner‟s conclusion that the combination of Hosoi,
Beltowski, Gray, and Davignon renders obvious the method of treating
atherosclerosis or hyperlipidemia in a human subject of claim 18. We thus
reverse the rejection of claims 18-25 under 35 U.S.C. § 103(a) as being
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rendered obvious by the combination of Hosoi, Beltowski, Gray, and
Davignon.

REVERSED

alw