Ex Parte Ahmad et al

Patent Trial and Appeal Board

Jun 6, 2016

12470219 (P.T.A.B. Jun. 6, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/470,219 05/21/2009
72960 7590 06/08/2016
Casimir Jones, S,C,
2275 DEMING WAY, SUITE 310
MIDDLETON, WI 53562
FIRST NAMED INVENTOR
AteeqAhmad
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.
JINA-13458/US-2/CIP 3433
EXAMINER
CHANNA V AJJALA, LAKSHMI SARADA
ART UNIT PAPER NUMBER
1611
NOTIFICATION DATE DELIVERY MODE
06/08/2016 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):
docketing@casimirjones.com
pto .correspondence@casimirjones.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ATEEQ AHMAD, SHOUKATH M. ALI, MOGHIS U. AHMAD,
SAIFUDDIN SHEIKH, and IMRAN AHMAD 1
Appeal2013-009952
Application 12/470,219
Technology Center 1600
Before ERIC B. GRIMES, MELANIE L. McCOLLUM, and
RICHARD J. SMITH, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating a neurodegenerative disease, which have been rejected for
obviousness and obviousness-type double patenting. We have jurisdiction
under 35 U.S.C. § 6(b).
We affirm.
1 Appellants identify the Real Party in Interest as Jina Pharmaceuticals, Inc.
(Appeal Br. 3.)
Appeal2013-009952
Application 12/470,219
STATEMENT OF THE CASE
"Tamoxifen is a selective estrogen receptor modulator (SERM).
Recent investigations strongly support a therapeutic role of estrogen/SERMs
in psychiatric diseases (e.g., bipolar disorder, schizophrenia) and a
neuroprotective effect in neurodegenerative conditions (e.g., multiple
sclerosis, Parkinson disease, Alzheimer disease, and stroke)." (Spec. i-f 5.)
"Tamoxifen use also showed improvement in manic symptoms in patients
with schizoaffective disorder." (Id.)
"Tamoxifen is extensively metabolized ... into active metabolites
including 4-hydroxy tamoxifen and 4-hydroxy-N-desmethyl tamoxifen
(endoxifen)." (Id. at i-f 9.) The Specification states that "[t]he use of
endoxifen as a therapeutic agent e.g., for cancer, and psychiatric and
neurodegenerative diseases has significant advantages compared to use of
the mother compound tamoxifen." (Id.)
Claims 1, 3-5, 7, 9, and 13-19 are on appeal. Claim 1 is the only
independent claim and reads as follows:
1. A method of treating a neurodegenerative disease in a subject,
comprising administering to said subject to a composition comprising
an effective amount of a complex comprising a purified synthetic
preparation of endoxifen, wherein said endoxifen is a free base or is in
the form of a salt.
In response to an election of species requirement, Appellants elected
treatment of bipolar disorder using orally administered tablets. (Appeal Br.
3.)
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Appeal2013-009952
Application 12/470,219
The claims stand rejected as follows:
Claims 1, 4, 5, 7, 13, and 14 under 35 U.S.C. § 103 as obvious based
on Einat2 or Manji, 3 in view of Lim4 (Ans. 5);
Claims 3, 9, 18, and 19 under 35 U.S.C. § 103 as obvious based on
Einat or Manji, in view of Lim and Neumann5 (Ans. 7);
Claims 3, 9, 15, and 18 under 35 U.S.C. § 103 as obvious based on
Einat or Manji, in view of Lim and Zeisig6 (Ans. 8);
Claims 16 and 17 under 35 U.S.C. § 103 as obvious based on Einat or
Manji, in view of Lim and Unger7 (Ans. 9--10); and
Claims 1, 3-5, 7, 9, and 13-19 based on obviousness-type double
patenting over the claims of U.S. Patent 9,333, 1908 in view of Einat, Manji,
Lim, Zeisig, Neumann, and Unger (Ans. 11 ).
2 Einat et al., Protein _l(_inase C Inhibition b}' Tamoxifen 14ntagonizes _l·vfanic-
Like Behavior in Rats: Implications for the Development of Novel
Therapeutics for Bipolar Disorder, 55 Neuropsychobiology 123-131
(2007).
3 Manji et al., Bipolar disorder: leads from the molecular and cellular
mechanisms of action of mood stabilisers, 178 British Journal of Psychiatry
s107-s119 (2001).
4 Lim et al., Endoxifen, a Secondary Metabolite of Tamoxifen, and 4-0H-
Tamoxifen Induce Similar Changes in Global Gene Expression Patterns in
MCF-7 Breast Cancer Cells, 318 Journal of Pharmacology and
Experimental Therapeutics 503-512 (2006).
5 Neumann, US 4,310,523, issued Jan. 12, 1982.
6 Zeisig et al., Reduction of tamoxifen resistance in human breast
carcinomas by tamoxifen-containing liposomes in vivo, 15 Anticancer Drugs
707-14 (2004).
7 Unger et al., US 6,638,767 B2, issued Oct. 28, 2003.
8 The Answer sets out a provisional obviousness-type double patenting
rejection based on application 12/515,261. (Ans. 11.) The '261 application
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Appeal2013-009952
Application 12/470,219
Issue
I
The Examiner has rejected claims 1, 4, 5, 7, 13, and 14 as obvious
based on either Einat or Manji, in view of Lim. The Examiner finds that
"Einat teaches that activated protein kinase C (PKC) levels ... may play a
major role in maniac [sic, manic] disorders." (Ans. 5.) The Examiner also
finds that Einat teaches that tamoxifen is a known PKC inhibitor and causes
"behavioral changes that model anti-manic effects." (Id.) The Examiner
finds that Manji also discloses that tamoxifen is a PKC inhibitor that has
anti-manic effects. (Id. at 6.)
The Examiner finds that Lim teaches that endoxifen is a metabolite of
tamoxifen that "is equipotent to 4-hydroxy-tamoxifen (4-0H-Tam) with
respect to estrogen receptor binding," and teaches that "the spectrum of
pharmacological activity and potency of endoxifen is quite similar to that of
4-0H-Tam." (Id.) "Lim suggest[s] that endoxifen is a major component of
the total tamoxifen activity in women taking tamoxifen." (Id.)
The Examiner concludes that it would have been obvious "to
substitute tamoxifen of Einat or Mani [sic] with endoxifen ... because Lim
teaches that endoxifen is equipotent as tamoxifen in its receptor binding
activity and both compounds have the same pharmacological activity." (Id.
at 6-7.) "Therefore, a skilled artisan would have expected endoxifen to be
equally effective in inhibiting the PKC as that oftamoxifen and thus treat
issued as U.S. Patent 9,333,190 (May 10, 2016), so the rejection is no longer
provisional.
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Appeal2013-009952
Application 12/470,219
not only breast cancer but also manic disorders such as bipolar disorder."
(Id. at 7.)
Appellants contend that Lim is directed to the antiestrogenic activity
of tamoxifen, rather than the PKC inhibition discussed by Einat and Manji.
(Appeal Br. 10-14.) Appellants also contend that Einat discloses that
tamoxifen was chosen for specific reasons, and the references do not show
that any of these reasons applied to endoxifen. (Id. at 14--15.) Appellants
argue that the references do not support a reasonable expectation that
endoxifen would share tamoxifen's PKC inhibiting activity. (Id. at 15.)
Finally, Appellants argue that the rejection relies on hindsight because there
is no suggestion to replace tamoxifen with endoxifen for PKC inhibition.
(Id. at 16-17.)
The issue presented is whether the evidence supports the Examiner's
conclusion that it would have been obvious to use endoxifen to treat bipolar
disorder, with a reasonable expectation of success.
Findings of Fact
1. Einat states that "[i]n a small clinical study, tamoxifen (a PKC
inhibitor) had antimanic efficacy." (Einat 123, left col.)
2. Einat states that tamoxifen is one of three known PKC inhibitors
approved for human use and that it has been safely used in women, men, and
children, including for the treatment of malignant glioma. (Id. at 128, right
col.)
3. Einat concludes that "it is reasonable to suggest that the [observed]
effects of tamoxifen are related to its PKC-inhibitory effect and that PKC
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Application 12/470,219
inhibition results in an antimanic-like effect in rat models of mania." (Id. at
129, bridging paragraph.)
4. Manji states that "[t]here is currently only one relatively selective
PKC inhibitor available for human use - tamoxifen." (Manji s 111, right
col.)
5. Manji states that some of the effects of tamoxifen are due to its
antiestrogenic activity but it is also a potent PKC inhibitor at therapeutically
relevant concentrations. (Id.)
6. Manji states that, "[i]n view of the apparent involvement of the
PKC signalling system in the pathophysiology of bipolar disorder ... PKC
inhibitors may be useful agents in its treatment." (Id. at sl 12, left col.)
7. Lim states that "endoxifen ... a pharmacogenetically regulated
metabolite oftamoxifen, is equipotent to 4-hydroxy-tamoxifen (4-0H-Tam)
with respect to estrogen receptor binding and inhibition of 17B-estradiol
(E2)-induced cell proliferation." (Lim 503, abstract.)
8. Lim states that "tamoxifen is metabolized in vitro and in vivo to
several metabolites of varying potency and antiestrogenicity .... Many of
the tamoxifen metabolites (e.g., N-desmethyl-tamoxifen, 4-hydroxy-
tamoxifen (4-0H-Tam), tamoxifen N-oxide, and a-hydroxy-tamoxifen) have
been characterized previously." (Id. at 503-504, left col.)
9. Lim states that "4-0H-Tam has been shown to exhibit 30- to 100-
fold higher potent antiestrogenic activity than that of tamoxifen .... For this
reason, tamoxifen has even been referred to sometimes as a prodrug that
requires conversion to its hydroxylated metabolite to exert its activity." (Id.
at 504, left col.)
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Application 12/470,219
10. Lim states that "endoxifen has pharmacological activity
comparable to that of 4-0H-Tam, with respect to its binding affinity to
estrogen receptors (ERs ), antiproliferative activity, and inhibitory effects on
the expression of typical estrogen-regulated genes in ER-positive breast
cancer cells." (Id.)
11. Lim states that "the plasma concentrations of endoxifen in
patients taking a commonly prescribed dose of tamoxifen (20 mg per day) is
on the average over 6-fold higher than that of 4-0H-Tam .... These data
prompted us to propose a working hypothesis that endoxifen could be a
more important contributor to tamoxifen activity than 4-0H-Tam." (Id.)
12. Lim concludes that results of a microarray analysis "strongly
suggest that the active tamoxifen metabolites, endoxifen and 4-0H-Tam,
have almost identical effects on the global pattern of gene expression in
human breast cancer cells." (Id. at 510, bridging paragraph.)
13. Lim states that the "data strongly suggest that 4-0H-Tam is not
the only active tamoxifen metabolite and that endoxifen is also a potent
selective estrogen receptor modulator that induces a similar expression
profile." (Id. at 510, right col.)
Analysis
We agree with the Examiner that Einat or Manji, in combination with
Lim, would have made obvious the method of claim 1. Both Einat and
Manji disclose that tamoxifen is a protein kinase C (PKC) inhibitor (FFl,
FF4). Einat states that tamoxifen is an effective antimanic agent (FFl, FF3).
Manji suggests treating bipolar disorder with PKC inhibitors (FF6).
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Application 12/470,219
Lim discloses that 4-0H-Tam, a metabolite of tamoxifen, is 30- to
100-fold more potent in antiestrogenic effect than tamoxifen itself, and
tamoxifen has been called a prodrug of 4-0H-Tam (FF9). Lim discloses that
plasma levels of endoxifen are, on average, six times higher than those of 4-
0H-Tam in patients taking tamoxifen (FFl 1 ).
Lim also discloses that endoxifen has pharmacological activity
comparable to that of 4-0H-Tam with respect to estrogen receptor binding,
antiproliferative activity, and inhibiting the expression of estrogen-regulated
genes (FF 10). Lim discloses that endoxifen and 4-0H-Tam have "almost
identical effects" on gene expression in breast cancer cells (FF12). Lim
discloses that endoxifen is also an active metabolite of tamoxifen (FF13).
It would have been obvious to substitute Lim's endoxifen for the
tamoxifen used in the methods of Einat or Manji, because Lim teaches that
endoxifen has pharmacological activity and an effect on gene expression that
are similar to those of 4-0H-Tam, another active metabolite that is a much
more potent antiestrogenic agent than tamoxifen itself. It would have been
reasonable to expect that both metabolites of tamoxifen would inhibit PKC,
and therefore be useful in the method of Einat or Manji, because tamoxifen
"requires conversion to its hydroxylated metabolite [ 4-0H-Tam] to exert its
activity" (FF9), and endoxifen has similar effects as 4-0H-Tam.
Appellants point out that Einat and Manji are both interested in the
PKC-inhibiting activity of tamoxifen, while Lim does not discuss that
particular activity. (Appeal Br. 10-12.) Appellants argue that Lim discloses
several metabolites of tamoxifen (id. at 12) and provides no basis for an
expectation that any given metabolite will share tamoxifen's PKC-inhibiting
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Application 12/470,219
activity (id. at 13-14). Similarly, Appellants argue that there would not have
been a reasonable expectation of success because Lim's disclosure relates to
antiestrogenic activity, not PKC inhibition. (Id. at 15.)
We are not persuaded. Tamoxifen was known to be converted into
different metabolites, including 4-0H-Tam and endoxifen (FF7, FF8). Lim
discloses that tamoxifen has been called a prodrug of 4-0H-Tam, which is a
much more potent antiestrogenic agent than tamoxifen (FF9); that endoxifen
has similar activity to 4-0H-Tam (FFlO, FF12); and that an average of six
times as much endoxifen is present in patients' plasma as compared to 4-
0H-Tam (FFl 1). As a result, it would have been reasonable for a skilled
worker to expect that the effects observed after administering tamoxifen,
including PKC inhibition (FF3, FF5), are at least partly due to its active
metabolites, including endoxifen. "[T]he expectation of success need only
be reasonable, not absolute." Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
1364 (Fed. Cir. 2007).
Appellants also argue that the references would not have led a skilled
worker to substitute endoxifen for tamoxifen because they do not suggest
that tamoxifen had deficiencies as a PKC inhibitor and Einat provides
specific reasons to use tamoxifen because it was a known PKC inhibitor
approved for human use and had previously been used in women, men, and
children. (Appeal Br. 14.) Appellants argue that "nothing in the cited art
suggests that replacing tamoxifen with endoxifen would be either successful
or advantageous for PKC inhibition in the treatment of neurodegenerative
disease." (Id. at 16.)
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Application 12/470,219
This argument is also unpersuasive. As discussed previously, the
cited references provide a reasonable expectation that endoxifen is at least
partly responsible for the effect of inhibiting PKC after tamoxifen is
administered to patients. Lim discloses that endoxifen shares similarities
with 4-0H-Tam in its estrogen receptor-binding, antiproliferative activity,
inhibition of estrogen-regulated genes (FF 10), and effect on gene expression
(FF12). Lim also discloses that 4-0H-Tam was known to be largely
responsible for tamoxifen's antiestrogenic activity (FF9), and that endoxifen
is found at higher levels than 4-0H-Tam in the plasma of patients taking
tamoxifen (FF 11 ). Thus, it would have been obvious to substitute an active
metabolite of tamoxifen, including endoxifen, based on an expectation that
tamoxifen's observed in vivo activities are at least partly due to conversion
to the active metabolites.
Conclusion of Law
The evidence supports the Examiner's conclusion that it would have
been obvious to use endoxifen to treat bipolar disorder, with a reasonable
expectation of success.
Claims 4, 5, 7, 13, and 14 have not been argued separately and
therefore fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
II
The Examiner has rejected claims 3, 9, and 15-19 as obvious based on
either Einat or Manji, combined with Lim and either Neumann, Zeisig, or
Unger.
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Application 12/470,219
Appellants argue only that "[t]he additional rejections under 103(a)
rely upon the same combination of Einat/Manji and Lim, and the
deficiencies in this combination are not remedied by Neumann, Zeisiq [sic],
or Unger." (Appeal Br. 15.)
Because Appellants have waived arguments based on Neumann,
Zeisig, or Unger, we affirm the rejection of claims 3, 9, 18, and 19 under
35 U.S.C. § 103 based on Einat or Manji, in view of Lim and Neumann; the
rejection of claims 3, 9, 15, and 18 under 35 U.S.C. § 103 based on Einat or
Manji, in view of Lim and Zeisig; and the rejection of claims 16 and 17
under 35 U.S.C. § 103 based on Einat or Manji, in view of Lim and Unger.
SeeHyattv. Dudas, 551F.3d1307, 1314 (Fed. Cir. 2008) ("When the
appellant fails to contest a ground of rejection to the Board, ... the Board
may treat any argument with respect to that ground of rejection as waived.
In the event of such a waiver, the PTO may affirm the rejection of the group
of claims that the examiner rejected on that ground without considering the
merits of those rejections.").
III
The Examiner has rejected claims 1, 3-5, 7, 9, and 13-19 for
obviousness-type double patenting over the claims of U.S. Patent 9,333, 190
in view of Einat, Manji, Lim, Zeisig, Neumann, and Unger.
Appellants state that they "have requested that a provisional rejection
on the grounds of nonstatutory obviousness-type double patenting over a
copending application be held in abeyance pending allowability of a claim in
this or in the co-pending application." (Appeal Br. 6.)
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Application 12/470,219
Because the claims of the previously co-pending application have
been allowed and Appellants have waived arguments disputing the merits of
the double patenting rejection, we affirm it. See Hyatt, 551 F .3d at 1314.
SUMMARY
We affirm all of the rejections on appeal.
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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