Ex Parte Kloog et al

Patent Trial and Appeal Board

Dec 12, 2016

13521637 (P.T.A.B. Dec. 12, 2016)

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
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/521,637 07/11/2012 Yoel Kloog RAMOT 3.3-024 1730
530 7590 12/14/2016
LERNER, DAVID, LITTENBERG,
KRUMHOLZ & MENTLIK
600 SOUTH AVENUE WEST
WESTFIELD, NJ 07090
EXAMINER
STRONG, TORI
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
12/14/2016 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte YOEL KLOOG, ELIZABETA AIZMAN, and JOAB CHAPMAN
Appeal 2015-005618
Application 13/521,6371
Technology Center 1600
Before JEFFREY N. FREDMAN, RYAN H. FLAX 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 a multiple sclerosis patient. 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 Kadmon Corporation.
App. Br. 4.
Appeal 2015-005618
Application 13/521,637
STATEMENT OF THE CASE
Claims 7—10, 12—17, and 19—22 are on appeal. Claim 7 is illustrative
and reads as follows:
wherein X represents S; wherein R1 represents famesyl,
or geranyl-geranyl; R2 is COOR7, CONR7R8, or
COOCHR9OR10, wherein R7 and R8 are each
independently hydrogen, alkyl, or alkenyl; wherein R9
represents H or alkyl; and wherein R10 represents alkyl;
and wherein R3, R4, R5 and R6 are each independently
hydrogen, alkyl, alkenyl, alkoxy, halo, trifluoromethyl,
trifluoromethoxy, or alkylmercapto; and glatiramer
acetate, wherein the glatiramer acetate is administered
subcutaneously.
The Examiner rejected claims 7—10, 12—17, and 19—22 under
35 U.S.C. § 103(a) as unpatentable over the combination of Kloog,2 Avila
Zaragoza,3 and Kreitman.4
2 Kloog et al., WO 00/78303 Al, published Dec. 28, 2000 (“Kloog”).
3 Avila Zaragoza et al., WO 2009/115634 Al, published Sept. 24, 2009 as
evidenced by US Patent Publication No. 2011/0015132 Al (“Avila
Zaragoza”).
4 Kreitman et al., WO 2006/089164 Al, published Aug. 24, 2006
(“Kreitman”).
7. A method for treating a multiple sclerosis patient
comprising co-administering to the patient
therapeutically effective amounts of a Ras antagonist
represented by the formula
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FINDINGS OF FACT
1. Kloog discloses:
An aspect of the present invention is directed to a method
for inhibiting Ras induced proliferation of cells
associated with a non-malignant disease, disorder or
pathological condition. The method entails administering
to a patient (a human or other mammal) a Ras antagonist
in an amount effective to inhibit the proliferation. The
invention is particularly directed to autoimmune diseases
characterized by a proliferation of T-cells (e.g., normal
T-cells) such as type 1 diabetes, lupus and multiple
sclerosis.
Kloog p. 3,11. 16—21.
2. Kloog discloses: “Preferred Ras antagonists include famesyl
thiosalicylic acid (FTS) and structurally related compounds or analogs
thereof, which are believed to function by displacing or dislodging Ras from
its membrane anchor.” Id. at p. 4,11. 5—8.
3. Avila Zaragoza discloses: “pathophysiology of MS is
multifaceted and it may be necessary to combine different drugs with
complementary mechanisms of action to obtain maximal clinical benefit in
patients who do not respond to conventional monotherapies. The main
clinical rationale for using drug combinations is obtaining additive or even
synergistic therapeutic effects.” Avila Zaragoza 14.
4. Avila Zaragoza discloses: “It has been described that, due to its
different mechanisms of action, glatiramer acetate may represent the ideal
candidate to accompany other agents to achieve complementary and
potentially synergistic therapeutic effects.” Id. 1 5.
5. Avila Zaragoza discloses:
Due to its vaccine-type mechanism of action, in order to
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be effective GA needs to induce an immune response
against GA mediated by CD4+. Since MTA suppresses
CD4+ activation, which is necessary for the generation of
GA-specific T cell responses, it could be expected that
the combination of MTA and GA could be neutral or
even harmful.
Id. 19.
6. Avila Zaragoza discloses: “Despite what could be expected, it
has now been surprisingly found that the combined administration of MTA
and GA to an MS animal model gives rise to a more potent
immunomodulatory activity compared to the administration of each of the
drugs separately.” Id. 110.
7. Avila Zaragoza discloses: “Boggild [Boggild. J Neural (2006),
253 (Suppl 6): VI/45-VI/51] and Ramtahal et al. [Ramtahal et al. J Neural
(2006); 253:1160-1164] used mitoxantrone as an induction therapy followed
by maintenance therapy with GA in a series of non-random, uncontrolled
observational cases, and observed a 90% reduction in the relapse rate among
patients.” Id. 1 5.
8. Avila Zaragoza discloses: “W02005009333 describes that
Copolymer 1 (GA)-related heteropolymers or peptides in combination with
other immunosuppressive drugs induce an unexpected synergistic effect, and
thus improve the efficacy of the current immunosuppressive regimens.” Id.
9. Kreitman discloses:
Glatiramer acetate (GA), also known as Copolymer-1,
has been shown to be effective in treating multiple
sclerosis (MS).... Daily subcutaneous injections of
glatiramer acetate (20 mg/injection) reduce relapse rates,
progression of disability, appearance of new lesions by
magnetic resonance imaging (MRI),. . . and appearance
of “black holes” . . . Glatiramer acetate reduces the
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proportion of MS lesions evolving into black holes.
Kreitmanp. 3,11. 15—29.
10. Kreitman discloses:
The subject invention provides a method of treating a
subject afflicted with a form of multiple sclerosis
comprising periodically administering to the subject an
amount of glatiramer acetate and an amount of rasagiline
or a pharmaceutically acceptable salt thereof, wherein the
amounts when taken together are effective to alleviate a
symptom of the form of multiple sclerosis in the subject
so as to thereby treat the subject.
Id. atp. 9,11. 1—10.
11. The only experimental data provided in the Specification is data
relying on “experimental autoimmune encephalomylelitis (EAE),” an
“animal model widely found useful for multiple sclerosis research.”
Specification | 55; Examples I—III.
ANALYSIS
Appellants argue claims 7—10, 12—17, and 19—22 as a group. We
designate claim 7 as representative for claims 7—10, 12—17, and 19—22.
The Examiner found that Kloog disclosed administration of
famesylthiosalicyclic acid (FTS) to treat multiple sclerosis, but did not teach
co-administration with glatiramer acetate (GA). Final Rej. 7.
The Examiner found that Avila Zaragoza disclosed that multiple
sclerosis has a multifaceted pathophysiology, potentially making it a
necessary to combine therapies for treatment. Id. at 8. The Examiner found
that Avila Zaragoza disclosed that GA is “an ideal candidate” for
combination therapy and that multiple sclerosis could be treated with the
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combination of GA and 5’-methylthioadenosine (MTA). Id. Avila
Zaragoza further teaches that the combined administration of GA and MTA
provides a benefit over the administration of either alone. Id.
The Examiner found that Kreitman disclosed that treating multiple
sclerosis with the combination of GA and rasigiline (a monoamine oxidase
inhibitor) provides benefits over administration of either alone. Id. at 8—9.
Based on the combined disclosures of Kloog, Avila Zaragoza, and
Kreitman, the Examiner concluded:
It would have been obvious to a person of ordinary skill in the
art at the time of invention to combine the teachings of Kloog
and Avila Zaragoza along with the example of Kreitman to co­
administer a Ras antagonist with glatiramer acetate because
prior teaching has indicated that coadministering any drug that
treats multiple sclerosis with glatiramer acetate should
predictably have added benefit. The Applicant has utilized an
alternative combination to address the same problem that exists
in the art.
Id. at 9. In response to Appellants’ arguments during prosecution, the
Examiner also cited Herges,5 Strive,6 Soos7 and Costello8 as providing
5 Herges et al., Neuroprotective Effect of Combination Therapy of
Glatiramer Acetate and Epigallocatechin-3-Gallate in Neuroinflammation,
6(10) PLoS ONE 1-9 (2011) (“Herges”).
6 Strive et al., Immunomodulatory Synergy by Combination of Atorvastatin
and Glatiramer Acetate in Treatment of CNS Autoimmunity, 116(4)
Journal of Clinical Investigation 1037-1044 (2006) (“Strive”).
7 Soos et al., Cutting Edge: Oral Type IIFN-t Promotes a Th2 Bias and
Enhances Suppression of Autoimmune Encephalomyelitis by Oral
Glatiramer Acetate, 169 Journal of Immunology 2231-2235 (2002)
(“Soos”).
8 Costello et al., Combination Therapies for Multiple Sclerosis: Scientific
Rationale, Clinical Trials, and Clinical Practice, 20 Current Opinion in
Neurology 281-285 (2007) (“Costello”).
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further evidence of the use of GA “as a co-administered agent to
produce synergistic therapy for MS.” Final Act. 5. The teachings of
these references are summarized in the Final Action. Id.
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 3—13; Final Act. 4—11) and agree
that the claims are obvious over Kloog, Avila Zaragoza, and Kreitman. We
address Appellants’ arguments below.
Appellants contend that the person of ordinary skill would not have
been able to predict the synergy achieved by the claimed drug combination.
As support, Appellants cite Avila Zaragoza’s teaching of “drawbacks”
deriving from GA therapy, App. Br. 13—14, Kreitman’s teaching that the
administration of two drugs to treat the same condition is unpredictable, id.
at 13, and the following passage from of Conway9:
Disease-modifying therapies have also been used in
combination with drugs approved for other indications, such as
corticosteroids, methotrexate, azathioprine, and
cyclophosphamide. Many preliminary studies have provided
favourable results for various combination regimens. However,
several subsequent large, randomized, controlled trials have had
negative or conflicting results. Therefore, the usefulness of
combination therapy in MS remains uncertain.
Id. at 15. We are not persuaded.
Avila Zaragoza expressly teaches that the pathophysiology of multiple
sclerosis may require a combination of different drugs to obtain maximal
clinical benefit and that “glatiramer acetate [GA] may represent the ideal
9 Conway et al., Combination Therapy in Multiple Sclerosis, 9(3) Lancet
Neuro. 299—308 (2010) (“Conway”). Conway was excerpted in the
December 13, 2013 Declaration of the inventor Joab Chapman.
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candidate to accompany other agents to achieve complementary and
potentially synergistic therapeutic effects.” FF3 and FF4. Further, both
Avila Zaragoza and Kreitman provide examples where GA was used
successfully in combination other drugs, specifically, MTA and rasagiline.
FF6 and FF10; see also FF7 and FF8 (discussing GA combination therapy
with mitoxantrone and with “other immunosuppressive drugs”). These
teachings provide a reasonable expectation that combination therapy with
GA would be effective. The general teaching of Kreitman that combination
therapy is unpredictable and Avila Zaragoza’s discussion of the drawbacks
of GA therapy do not diminish this expectation of success, particularly as
both Kreitman and Avila Zaragoza provide examples of successful GA
combination therapy.
Conway’s discussion of the uncertainty of combination therapy in
multiple sclerosis patients likewise does not diminish the expectation of
success. The uncertainty taught by Conway is in the context of human trials
and, indeed, Conway notes that preliminary animal studies of combination
therapy provided favorable results. Conway Abstract. This vitiates
Appellants’ argument because Appellants rely on data only from animal
studies. See FF11. We agree with the Examiner that “Appellants can’t now
argue that while [the] art demonstrates synergy in EAE models but not in
human trials, [] the instant combination demonstrating synergy in EAE
models with no human trials is now unexpected.” See Ans. 9—10.
Appellants argue that the skepticism of the inventor, Dr. Joab
Chapman,10 reflects the nonobviousness of the claimed combination. App.
Br. 16—19. Dr. Chapman states “[a]t the inception of the project, and before
10 Declaration of Joab Chapman, dated Dec. 31, 2013 (“Chapman Decl.”).
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any experiments were initiated, my personal belief was that the combination
of FTS and glatiramer acetate (GA) would not be beneficial in the treatment
of multiple sclerosis.” Chapman Decl. 2. Dr. Chapman explains:
My belief was based on the knowledge that GA is an
immunomodulator and is dependent on the immune system
being stimulated whereas FTS is a suppressor of the immune
system. Thus, I believed that the use of FTS had the potential
of counteracting the stimulatory effects of GA. I did not [at] all
expect the results that we achieved.
Id. We acknowledge Dr. Chapman’s initial skepticism, but are not
persuaded that it renders the claimed invention nonobvious.
We have broad discretion as to the weight to give to declarations
offered in the course of prosecution. In re Am. Acad. ofSci. Tech. Ctr., 367
F.3d 1359, 1368 (Fed Cir. 2004). Here, we agree with the Examiner that Dr.
Chapman’s skepticism mirrors that expressed in Avila Zaragoza. See Ans.
10. Both Dr. Chapman and Avila Zaragoza expressed skepticism about the
effectiveness of combination therapy with GA and an immunomodulator.
Compare FF5 and FF6 with Chapman Decl. 2. Both explained that they
expected that an immunosuppressant (MTA in the case of Avila Zaragoza
and FTS in Chapman’s case) would counteract the effects of GA, which acts
by stimulating the immune system. Id. Avila Zaragoza teaches that this
skepticism is misplaced and that an immunosuppressant may indeed exhibit
synergistic effects when used with GA. FF6.
Appellants argue that Avila Zaragoza’s teaching that the combination
of MTA and GA exhibits synergism would not have caused one to expect
that FTS would exhibit synergism with GA because of the differences
between MTA and FTS with respect to structure, cellular mode of action and
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immunological effects. App. Br. at 19. As support, Appellants cite the
Chapman Declaration, which states:
The differences between the FTS and MTA are substantial.
They are structurally distinct, have a completely different
cellular mode of action, and exert different immunological
effects. 5’-Methylthioadenosine (MTA) is a naturally occurring
sulfur-containing nucleoside present in all mammalian tissues.
MTA is produced from S-adenosylmethionine mainly through
the polyamine biosynthetic pathway, where it behaves as a
powerful inhibitory product. FTS is a synthetic compound
which is analogous to the famesylated signaling proteins such
as Ras and inhibits their activity by competing with their
membrane binding sites. Another important difference is how
the two agents exert their immunological effect. As described
in Avila Zaragoza, MTA acts on CD4 cells. As reported in
Aizman et al., 2010 and in earlier literature,. . . [inhibition of
Ras attenuates the course of experimental autoimmune neuritis.
. . . FTS acts by inhibiting both CD4 and CD8 cells. Based on
these differences, my professional opinion is that the results
reported in Avila Zaragoza would not have suggested that the
combination of FTS and GA is synergistic.
Chapman Decl. 5—6 (internal citations omitted). We are not persuaded.
Both MTA and FTS are immunosuppressants used to treat multiple
sclerosis. The principal difference between MTA and FTS, as explained by
Dr. Chapman, is that MTA acts on CD4 cells while FTS acts on both CD4
and CD8 cells. While Dr. Chapman provides his professional opinion with
respect to the cumulative effects of the differences between MTA and FTS,
Appellants do not provide persuasive evidence that FTS’s additional action
through CD8 cells would distinguish it from MTA with respect to its
potential to act synergistically with GA. Accordingly, we agree with the
Examiner that “Appellants have not clearly shown how the initial skepticism
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that was solved by Avila [Zaragoza] is different from the instant skepticism
provided by the expert’s declaration.” Ans. 10.
Appellants contend that the additional evidence of synergistic GA
combination therapy relied upon by the Examiner — i.e., Herges, Strive,
Soos, and Costello — is “not probative of obviousness.” App. Br. 20.
Appellants argue that Herges, Strive, and Soos do not support obviousness
based on considerations derived from testing in humans. Id. at 21. We are
not persuaded at least because, as the Examiner explained “[e]ach disclosure
explicitly teaches that synergistic benefit is achieved when combining GA to
a plurality of therapeutic agents in an EAE animal model.” Ans. 11. As
discussed above, Appellants rely solely on data from an EAE animal model.
See supra p. 8—9; see also FF11.
Appellants contend that Costello does not support a finding of
obviousness based on Dr. Chapman’s disagreement with Costello’s
statement that GA is “the ideal candidate to partner with other agents to
achieve complementary and potentially synergistic effects.” App. Br. 22;
Costello 283. The reasons for Dr. Chapman’s disagreement with Costello
are similar to the reasons Dr. Chapman provided for not expecting the
combination of FTS and glatiramer acetate (GA) to be effective when he
initiated his project. For the reasons already discussed in connection with
that argument, we are not persuaded. See supra p. 9—10.
Accordingly, we affirm the Examiner’s decision to reject claim 7 as
obvious over the combination of Kloog, Avila Zaragoza, and Kreitman.
Because they were not argued separately, 8—10, 12—17, and 19—22 fall with
claim 7.
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SUMMARY
For these reasons and those set forth in the Examiner’s Answer, the
Examiner’s final decision to reject claims 7—10, 12—17, and 19—22 is
affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1).
AFFIRMED
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