Ex Parte Schulte et al

Patent Trial and Appeal Board

Jul 30, 2018

13990854 (P.T.A.B. Jul. 30, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/990,854 07/31/2013
23628 7590 08/01/2018
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC A VENUE
BOSTON, MA 02210-2206
UNITED ST A TES OF AMERICA
FIRST NAMED INVENTOR
Joost Schulte
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.
M0656.70218US02 8741
EXAMINER
PAGONAKIS, ANNA
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
08/01/2018 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):
Patents_eOfficeAction@WolfGreenfield.com
WGS_eOfficeAction@WolfGreenfield.com
PTOL-90A (Rev. 04/07)
UNITED ST ATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOOOST SCHLTE, KATHARINE JULIA SEPP,
and J. TROY LITTLETON1
Appeal 2017-009108
Application 13/990,8542
Technology Center 1600
Before RICHARD M. LEBOVIT Z, ULRIKE W. JENKS, and RICHARD J.
SMITH, Administrative Patent Judges.
LEBOVIT Z, Administrative Pa tent Judge.
DECISION ON APPEAL
This is an appeal from the Examiner's rejection under 35 U.S.C.
§§ 102 and 103 of claims directed to methods of treating Huntington's
disease with carbenoxolone. We have jurisdiction for this appeal under
35 U.S. C. § 6(b ). The rejections are reversed, but new grounds of rejection
are set forth pursuant to 37 C.F.R. § 4I.50(b).
1 The Appeal Brief ("Appeal Br.") 3 lists Massachusetts Institute of
Technology as the real party in interest and states that Oxalys
Pharmaceuticals, Inc., a Canadian corporation, is an exclusive licensee of the
application.
2 "The '854Application."
Appeal 2017-009108
Application 13/990,854
STATEMENT OF CASE
The claims stand fmally rejected by the Examiner as follows:
Claims 1, 4, 5, 9, 10, 92, 94, 98, and 99under 35 U.S.C. § 102(b)
(pre-AIA) as anticipated by Oksenberg(U.S. Pat. Appl. Publ. No.
2005/0137209 Al, June 23, 2005) as evidenced by Shao (Human Molecular
Genetics, 2007, 16(2): Rl 15-R123). Examiner's Answer ("Ans.") 2.
Claims 1, 4, 5, 9, 10, 92-95, 98, and 99under 35 U.S.C. § 103(a)
(pre-AIA) as obvious over Wilckens (U.S. Pat. Appl. Publ. No.
2008/0153791 Al, published Jun. 26, 2008) as evidenced by Shao. Ans. 4.
Claims 1, 4, 5, 9, 10, 92-95, 98, and 99under 35 U.S.C. §103(a) (pre-
AIA) as obvious over Cohen (WO 2012/117073 A2, published Mar. 1,
2012)3 as evidenced by Shao. Ans. 5.
Independent claim 1, which is illustrative of the appealed subject
matter, reads as follows:
1. A method for treating Huntington's disease, comprising
administering to a subject having Huntington's disease, an
effective amount of carbenoxolone or 18P-Glycyrrhetinic acid,
or an analog, salt, or solvate thereof, thereby treating the subject
having Huntington's disease.
REJECTIONS
Claim 1 is directed to administering "an effective amount of
carbenoxolone or 18P-Glycyrrhetinic acid, or an analog, salt, or solvate
thereof' to treat a subject having Huntington's disease. Carbenoxolone is an
analog of 18P-Glycyrrhetinic acid. Spec. 28; 27-28; 65:23-24.
3 The publication date of Cohen is after the priority date of April 15, 2011
accorded to the rejected claims. However, the priority dates of the Cohen
application are March 1, 2011 and March 29, 2011.
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Application 13/990,854
In response to a requirement to elect a species of claim 1, Appellants
elected carbenoxolone. Response to Species Election Requirement 2 (May
13, 2014 ). Appellants stated in the Appeal Brief that claim 93, directed to
the non-elected 18P-Glycyrrhetinic acid species, was "rejoined without
reason or comment by the Examiner in the Office Action mailed on May 18,
2015." Appeal Br. 3 (fn. 2). While the Examiner did not directly respond to
Appellants' statement, the Examiner stated in the Answer that the elected
species is carbenoxolone (Ans. 2), consistent with the Examiner's position
throughout prosecution (Final Act. 2-3). Consequently, we consider
carbenoxolone to be the elected species and the subject of this appeal.
Claim 92 is directed to treatment with the elected species carbenoxolone.
Claim 93 is directed to treatment with 18P-Glycyrrhetinic acid; however,
this is unelected subject matter, despite being included in the statement of
the rejection.
All three of the appealed rejections are based on the Examiner's
fmdings that each of Oksenberg, Wilckens, and Cohen describe treating
Huntington's disease with carbenoxolone. Ans. 3, 4, and 5. The Examiner
cited Oksenberg's disclosure as anticipatory to the claims, and Wilckens and
Cohen as rendering the claims obvious because the Examiner found that the
selection of Huntington's disease and carbenoxolone from the lists in
Wilckens and Cohen was necessary to have arrived at the claimed subject
matter. Id. Shao was cited by the Examiner as evidence that Huntington's
disease is a polyglutamine disease which expresses the Huntingtin protein
having a polyQ tract of36-121 residues, a limitation recited in some of the
dependent claims. Id. 3.
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Application 13/990,854
In response to the rejections, Appellants provided a declaration by
Katharine Sepp, Ph.D. ("Sepp Deel."), a co-inventor of the '854 Application.
Sepp Deel. ,r 2. Dr. Sepp provided evidence in her declaration that
carbenoxolone is toxic at the intraperitoneal and intravenous dosages utilized
in Oksenberg. Id. ,r,r 28-32. Dr. Sepp also stated in her declaration that the
skilled worker, reading Oksenberg, Wilckens, and Cohen, would have
considered "whether the prophetic treatments disclosed therein are viable,
taking into consideration various factors that include pharmacological
considerations such as ... toxicology profiles." Id. ,r 17. Dr. Sepp also
provided evidence that carbenoxolone does not cross the blood brain barrier.
Id. ,r,r 34--3 7.
Oksenberg Rejection
Dr. Sepp provided factual evidence, including citing several
publications, that the amounts of carbenoxolone administered to rats in
Example 2 of Oksenbergwere at a toxic dose level. Sepp Deel. ,r,r 28-32.
Example 2 of Oksenberg is model of cerebral ischemia. Oksenberg ,r 117.
Dr. Sepp further testified in her declaration that "[b ]ased on the description
and data in Oksenberg, a skilled artisan would thus not conclude that a toxic
level carbenoxolone dose which shows histological 'neuroprotection' could
provide functional 'neuroprotective' effects in a live animal." Sepp Deel.
,r 31. Dr. Sepp also cited a post-filing publication co-authored by
Oksenbergthat carbenoxolone results in complete lethality of all animals
within 7 days post-treatment when used to treat ischemia in rats. Id. Dr.
Sepp stated that in light of the "knowledge of carbenoxolone toxicology and
'neuroprotective' anti-ischemic dose ranges," the skilled worker would not
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Application 13/990,854
have read Oksenberg as teaching "the use of carbenoxolone as a
'neuroprotective' drug for the treatment of HD [Huntington's disease],
especially since HD is a genetic and chronic neurodegenerative disease that
would require a chronic dosing of a drug that only achieves its therapeutic
effect at a lethal toxic level in the model system employed by Oksenberg."
Id. ,r 32. Thus, Appellants argue that "Oksenbergis not an operable
disclosure because the dosage shown to provide neuroprotective effects in
the ischemia model was well known in the art to be toxic and lethal to
rodents." Appeal Br. 7.
The Examiner stated that "Appellant has provided nothing more than
allegations in the absence of facts to support his assertion that Oksenberg is
not enabled for the treatment of Huntington's disease." Ans. 7-8.
We do not agree with the Examiner on this point. Dr. Sepp cited
specific evidence in her declaration, including several pre-filing date
publications, of the toxicity of carbenoxolone and explained why such
knowledge would not have led the skilled worker to read Oksenberg as
teaching how to use the drug to treat Huntington's disease. Thus, the
guidance described in Oksenberg for administering carbenoxolone to treat
Huntington's disease would not have necessarily led to success in its
treatment because the dosages indicated in Example 2 of Oksenberg could
have been toxic. Anticipation "may not be established by probabilities or
possibilities. The mere fact that a certain thing may result from a given set
of circumstances is not sufficient." In re Robertson, 169 F.3d 743, 745 (Fed.
Cir. 1999) (internal citation and quotation marks omitted).
Because the Examiner did not provide adequate reason or evidence to
disbelieve or discredit Dr. Sepp' s declaration, we conclude that Oksenberg is
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Application 13/990,854
not enabled for the claimed method treating Huntington's disease with
carbenoxolone.
The rejection of claims 1, 4, 5, 9, 10, 92, 94, 98, and 99 as anticipated
by Oksenberg is reversed.
OBVIOUSNESS BASED ON WILCKENS AND COHEN
The rejections relying on Wilckens and Cohen are based on the
obviousness of utilizing carbenoxolone to treat Huntington's disease. It is
not disputed that both publications describe the drug and its use to treat
disease. Ans. 4, 5.
Appellants contend that it would not have been obvious to treat
Huntington's disease with carbenoxolone "because it is well established that
parenterally-dosed carbenoxolone does not penetrate the brain in detectible
quantities." Appeal Br. 16. The underlying premise of this argument is that
carbenoxolone must cross the blood brain barrier to have its therapeutic
effect. The '854 Application discloses that carbenoxolone targets 11-beta-
hydroxysteroid dehydrogenase 1 (HSD 1 ), "a brain enzyme that regulates the
production of cortisol in the brain" ('854 App. 31 :67), which is consistent
with the premise that the drug must cross the blood barrier to treat
Huntington's disease. Accordingly, because this issue was not disputed by
either the Examiner or Appellants, for the purpose of deciding this appeal,
we adopt the fmding that carbenoxolone must cross the blood barrier to treat
Huntington's disease.
Dr. Sepp provided evidence that carbenoxolone was known at the
time of the invention not to cross the blood brain barrier. Sepp Deel.
,r,r 34--3 7. Based on this evidence, Dr. Sepp stated:
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Application 13/990,854
[ A] skilled artisan would not deem Wilckens as teaching a
viable treatment of HD, owing to the known pharmacological
properties of carbenoxolone indicating that it cannot penetrate
the blood-brain barrier to inhibit the HSD 1 enzyme and
thereby elicit a beneficial effect in the brain.
Id. ,r 38. Dr. Sepp made a similar statement about Cohen. Id. ,r,r 45, 46.
The Examiner did not fmd this argument persuasive because of
statements in the Specification by the inventors that carbenoxolone can cross
the blood brain barrier. Ans. 8 (citing 31:15-16 and43:19 of the '854
Application). However, the statements in the '854 Application referenced
by the Examiner are not supported by factual evidence that it was known at
the time of the invention that carbenoxolone could cross the blood brain
barrier. As discussed by Dr. Sepp, there is evidence that it did not. Sepp
Deel. ,r,r 34--3 7. For example, the publication by Takeuchi, 4 cited by
Appellants, states that carbenoxolone disodium "hardly penetrate[ s] the BBB
[blood brain barrier]." Takeuchi 2. The publication by Leshchenko 5 also
concluded that carbenoxolone does not cross the blood brain barrier.
Leshchenko cited an earlier study which suggested that carbenoxolone did
cross the blood brain barrier, but explained that the earlier study only had
indirect evidence of this, and their own work showed that carbenoxolone did
not penetrate the blood brain barrier. Leshchenko 2. Thus, based on the
evidence before us, we conclude that it would not have been reasonably
expected that carbenoxolone, when administered systemically and outside
4 Takeuchi et al., PLoS ONE, June 2011, 6(6): 1-13 (e21108). Takeuchi was
published June 21, 2001, which is after the priority date of April 15, 2011
accorded by the Examiner. However, it relies on earlier publications for this
fact.
5 Leshchenko et al., BMC Neuroscience, 2006, 7(3):1-3. Submitted on Oct.
15, 2015 with PTO-Form 1449 (Information Disclosure Statement).
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Application 13/990,854
the blood brain barrier, would treat Huntington's disease. An obviousness
determination requires finding both that a skilled artisan would have been
motivated to combine the teachings of the prior art and that the skilled
artisan would have had a reasonable expectation of success in doing so.
Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367
(Fed. Cir. 2016).
Accordingly, we reverse both obviousness rejections based on
Wilckens and Cohen because the Examiner did not establish there would
have been a reasonable expectation of success that carbenoxolone could be
used to treat Huntington's disease.
NEW GROUNDS OF REJECTION
Leshchenko, however, suggested intracerebral injection of
carbenoxolone to circumvent the inability of carbenoxolone to cross the
blood brain barrier. Leshchenko 2. Leshchenko teaches:
Id.
Hence, intracerebral injections are strongly recommended if the
study is concerned with possible brain effects of the drug. In
addition, intracerebral administration circumvents the potential
confounding factor of systemic effects, which may be mediated
by mineralocorticoid receptor activation and could contribute to
the observed results.
Independent claim 1 does not exclude intracerebral injection of
carbenoxolone as suggested by Leshchenko. Consequently, based on
Leshchenko, one of ordinary skill in the art would have had reason to
administer carbenoxolone by intracerebral injection to circumvent the blood
brain barrier and to avoid carbenoxolone toxicity when administered by
intraperitoneal or intravenous injection (Sepp Deel. ,r 28).
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Application 13/990,854
Accordingly, the subject matter of claims 1 and 92 would have been
obvious to one of ordinary skill in the art based on (1) Wilckens and
Leshchenko, as evidenced by Shao; (2) Cohen and Leshchenko, as
evidenced by Shao; and (3) Oksenbergand Leshchenko, as evidenced by
Shao. Because the rationale differs from the Examiner's, and Leshchenko is
newly cited in the rejection, the rejections are set forth as new grounds
pursuant37 C.F.R. §4I.50(b).
We leave it to the Examiner to determine the obviousness of the
dependent claims. However, we note that claims 9 and 98 are limited to oral
administration. Dr. Sepp' s declaration establishes that one of ordinary skill
in the art would not have administered carbenoxolone orally or other
systemic routes because ofits inability to cross the blood brain barrier.
The new grounds of rejection are as follows:
Claims 1 and 92 are rejected under 35 U.S.C. 103(a) as obvious in
view ofWilckens andLeshchenko, as evidenced by Shao.
Claims 1 and 92 are rejected under 35 U.S.C. 103(a) as obvious in
view of Cohen and Leshchenko, as evidenced by Shao.
Claims 1 and 92 are rejected under 35 U.S.C. 103(a) as obvious in
view of Oksenberg and Leshchenko, as evidenced by Shao.
TIME PERIOD FOR RESPONSE
This Decision contains a new ground of rejection pursuant to
37 C.F.R. § 4I.50(b). Section4I.50(b)provides "[a] new ground of
rejection pursuant to this paragraph shall not be considered final for judicial
review." Section 41. 5 O(b) also provides:
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Application 13/990,854
When the Board enters such a non-fmal decision, the appellant,
within two months from the date of the decision, must exercise
one of the following two options with respect to the new ground
of rejection to avoid termination of the appeal as to the rejected
claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating to
the claims so rejected, or both, and have the matter reconsidered
by the examiner, in which event the prosecution will be
remanded to the examiner. The new ground of rejection is
binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the opinion
of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the
claims, appellant may again appeal to the Board pursuant to this
subpart.
(2) Request rehearing. Request that the proceeding be
reheard under § 41. 5 2 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in the MPEP § 1214.01.
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 ). See 37 C.F.R.
§§ 41.50(±), 4I.52(b).
REVERSED
37 C.F.R. § 4I.50(b)
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