Peter A. Virsik et al.

Patent Trials and Appeals Board

Aug 20, 2019

13906155 - (D) (P.T.A.B. Aug. 20, 2019)

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.
13/906,155 05/30/2013 Peter A. Virsik P233022.US.02
(X-0182 R1)
6553
20786 7590 08/20/2019
KING & SPALDING
1180 PEACHTREE STREET , NE
ATLANTA, GA 30309-3521
EXAMINER
DECK, JASON A
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
08/20/2019 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):
ATLIPDOCKETING@kslaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte PETER A. VIRSIK, DAVID J. WUSTOW,
THAMIL ANNAMALAI, and SURESH K. MANTHATI
__________

Appeal 2018-0020431
Application 13,906,155
Technology Center 1600
__________

Before DEBORAH KATZ, JOHN G. NEW, and JOHN E. SCHNEIDER,
Administrative Patent Judges.

SCHNEIDER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) from the Examiner’s
rejection of claims to compounds for treating multiple sclerosis or psoriasis
that have been rejected as obvious and for obviousness-type double
patenting.2 We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 Appellants identify Xenoport, Inc., as the real party in interest. Appeal Br.
3.
2 We have considered and herein refer to the Specification filed May 30,
2013 (“Spec.”); Final Office Action mailed Jan. 11, 2017 (“Final Act.”);
Appeal Brief filed June 12, 2017 (“Appeal Br.”); Examiner’s Answer mailed
Oct. 18, 2017 (“Ans.”); and Reply Brief filed Dec. 18, 2017 (“Reply Br.”).

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STATEMENT OF THE CASE
Fumaric acid esters have been used to treat psoriasis for many years.
Spec. ¶ 3. Oral administration of diemthyl fumarate has shown promising
results in reducing symptoms of multiple sclerosis. Id. ¶ 8. Oral
administration of these compounds often results in unwanted side effects
such as serious digestive tract irritation with attendant nausea, vomiting,
abdominal pain and diarrhea. Id. ¶¶ 7–8. The Specification discloses
“improved methods of treating multiple sclerosis and/or psoriasis in human
patients using fumaric acid esters. The methods are able to achieve high
therapeutic levels of [methyl hydrogen fumarate] in the blood plasma of a
patient without causing significant gastrointestinal irritation.” Id. ¶ 10.
Claims 1, 2, 11, 14–18, 20–22, 32, 36, and 37 are on appeal.3 Claim 1
is the sole independent claim and reads as follows:
1. A method of treating multiple sclerosis in a human
patient in need of such treatment, comprising orally
administering to the patient a compound of (I):

(I)
or a pharmaceutically acceptable salt thereof,
wherein:
R1 and R2 are independently chosen from hydrogen,
C1-6 alkyl, and substituted C1-6 alkyl;

3 Claims 4, 7, 10, 12, 25–31, and 33–35 are pending in the application but
have been withdrawn from consideration. Final Act. 2.
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R3 and R4 are independently chosen from hydrogen,
C1-6 alkyl, substituted C1-6 alkyl, C1-6 heteroalkyl,
substituted C1-6 heteroalkyl, C4-12 cycloalkylalkyl,
substituted C4-12 cycloalkylalkyl, C7-12 arylalkyl, and
substituted C7-12 arylalkyl; or R3 and R4 together with the
nitrogen to which they are bonded form a ring chosen
from a C4-10 heteroaryl, substituted C4-10 heteroaryl, C4-10
heterocycloalkyl, and substituted C4-10 heterocycloalkyl;

n is an integer from 0 to 4; and

X is independently chosen from a single oxygen
atom and a pair of hydrogen atoms;

wherein each substituent group is independently
chosen from halogen, -OH, -CN, -CF3 , =O, -NO2, benzyl,
-C(O)NR112, -R11, -OR11, -C(O)R11, -COOR11, and -NR112
wherein each R11is independently chosen from hydrogen
and C1-4 alkyl;

and wherein when X is a single oxygen atom, the
oxygen atom is connected to the carbon to which it is
bonded by a double bond to form a carboxyl group and
when X is a pair of hydrogen atoms, each hydrogen atom
is connected to the carbon to which it is bonded to by
single bond,

said oral administration being sufficient to obtain (i)
a therapeutic concentration of MHF in blood plasma of the
patient of at least 0.5 μg/ml at a time within 24 hours after
said oral administration; and (ii) an area under a
concentration of MHF in blood plasma versus time curve
(AUC) of at least 4.8 μg-hr/ml over 24 hours after start of
the oral administration, and wherein

a) the MHF prodrug exhibiting an average gastrointestinal
irritation score in an Annamalai-Ma gastrointestinal
irritation rat model of no more than 1.5 after orally
administering a solution or suspension the prodrug to rats
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at a dose of 180 mg-equivalents of methyl hydrogen
fumarate (MHF) per kg of body weight, dosed once per
day over 4 consecutive days, or

b) the MHF prodrug exhibits a relative GST enzyme activity
(GSTArel) of less than 80%, where GSTArel is calculated in
accordance with equation (I):

GSTArel (%) = (SARprodrug ÷ SARDMF) x 100 (I)
and SARprodrug is the specific activity ratio of the MHF
prodrug, and SARDMF is the specific activity ratio of
dimethyl fumarate, or both a) and b).

The claims stand rejected as follows:
Claims 1, 2, 11, 14–18, 20–22, 32, 36, and 37 have been rejected
under 35 U.S.C. § 103(a) as unpatentable over Gangakhedkar,4 in view of
Sagi.5
Claims 1, 2, 11, 14–18, 20–22, 32, 36, and 37 have been rejected for
non-statutory obviousness-type double patenting over claims 19–29 of US
8,952,006 B2.
Claims 20 and 21 have been rejected for non-statutory obviousness-
type double patenting over claims 19–29 of US 8,952,006 B2 in view of
Gangakhedkar.
Claims 1, 2, 11, 14–18, 20–22, 32, 36, and 37 have been rejected for
non-statutory obviousness-type double patenting over claims 19–29 of USS
13/973,700.

4 Gangakhedkar, et al, WO 2010/022177 A2; published Feb. 25, 2010
(“Gangakhedkar”).
5 Sagi et al., US 2005/0101779 A1; published May 12, 2005 (“Sagi”).
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DOUBLE PATENTING
Appellants have offered no substantive argument regarding this
rejection other than to ask that it be held in abeyance until allowable subject
matter has been found in the present application. Appeal Br. 17–18. We
therefore summarily affirm this rejection. 37 C.F.R. § 41.37(c)(iv).
OBVIOUSNESS
Issue
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
the claims would have been obvious over Gangakhedkar combined with
Sagi.
The Examiner finds that Gangakhedkar teaches the administration of
prodrugs of methyl hydrogen fumarate to treat multiple sclerosis. Final Act.
5. The Examiner finds that Gangakhedkar exemplifies fumarate prodrugs
having the following structures:

Id. at 6. The Examiner finds that Gangakhedkar teaches that the use of
prodrugs results in “increased gastrointestinal permeability and absorption,
improved solubility, and minimal cleavage in the gut lumen.” Id. at 5. The
Examiner also finds that Gangakhedkar teaches the use of enteric coatings.
Id. at 6.
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The Examiner finds that Sagi teaches a method for treating multiple
sclerosis using prodrugs with carbonyl masking groups. Id. The Examiner
finds that one of the masking groups used in Sagi is identical to one used in
Gangakhedkar and several others, shown below, have high homology to the
prodrug moieties used in Gangakhedkar.

Final Act. 6 (citing Sagi 28–29).
The Examiner concludes
It would have been obvious to one of ordinary skill in the
art at the time of filing of the instant invention to make and use
methyl hydrogen fumarate prodrugs with the prodrug moieties
of Sagi et al. and use them in the method of Gangakhedkar et al.
with an enteric coating that inhibits release in the stomach.

One of ordinary skill would have been motivated to make
and use the instantly claimed compounds because
Gangakhedkar et al. teaches that prodrugs of methyl hydrogen
fumarate offer improved features over methyl hydrogen
fumarate, and teaches the general type of prodrug moieties,
while Sagi et al. discloses additional prodrug moieties for
carboxylate groups that are of the same general type. The
skilled artisan would have used the prodrug moieties of Sagi et
al. for the method of Gangakhedkar et al. during the routine
optimization of the properties of the compounds, and would
have done so with a reasonable expectation of success in
making an improved treatment for multiple sclerosis.

One of ordinary skill would have been motivated to use
the composition with an enteric coating that inhibits release in
the stomach because these common formulations are well
known to the skilled artisan, and Gangakhedkar et al. teaches
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that they are useful for the administration of MHF prodrugs in
the treatment of multiple sclerosis. One skilled in the art would
have used an enteric coating that inhibits release in the stomach
for the MHF prodrug of Gangakhedkar et al. and Sagi et al.
with a reasonable expectation of success in making an
improved formulation for the treatment of multiple sclerosis.

Final Act. 7.
Principles of Law
[T]he examiner bears the initial burden, on review of the
prior art or on any other ground, of presenting a prima facie
case of unpatentability. If that burden is met, the burden of
coming forward with evidence or argument shifts to the
applicant.

After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.

In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
“[W]hen a patent claims a structure already known in the prior art that
is altered by the mere substitution of one element for another known in the
field, the combination must do more than yield a predictable result.” KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (citing United States v.
Adams, 383 U.S. 39, 50–51 (1966)).
Analysis
We adopt the Examiner’s findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer regarding this rejection. We find the Examiner has established that
the subject matter of the claims would have been obvious to one of ordinary
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skill in the art at the time the invention was made over Gangakhedkar
combined with Sagi. Appellants have not produced evidence showing, or
persuasively argued, that the Examiner’s determinations on obviousness are
incorrect. Only those arguments made by Appellants in the Briefs have been
considered in this Decision. Arguments not presented in the Briefs are
waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We have identified claim 1
as representative; therefore, all claims fall with claim 1. We address
Appellants’ arguments below.
Appellants contend that the references either alone or in combination
do not teach or suggest the claimed compound. Appeal Br. 8. Appellants
argue that the prodrugs disclosed in Gangakhedkar contain an additional
carbonyl group at the carbon alpha to the nitrogen and Sagi is directed to
prodrugs of phenylalanine derivatives and not methyl hydrogen fumarate.
Id. Appellants argue that Sagi does not teach or suggest that the masking
moieties disclosed therein can be used with other drug compositions. Id. at
9.
Appellants also argue that even if one skilled in the art were motivated
to use the prodrug moieties of Sagi with the fumarate of Gangakhedkar, it
would not result in the claimed compound but would produce a compound
with the following structure:

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See id. at 9.
We have considered Appellants arguments and are not persuaded that
the Examiner’s rejection is in error.
Appellants’ arguments about the teachings of the individual references
is not persuasive as it is the combined teachings of the references that serves
as the basis for this rejection. “Non-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references. [The reference] must be read, not
in isolation, but for what it fairly teaches in combination with the prior art as
a whole.” In re Merck & Co. Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
Gangakhedkar teaches the preparation of prodrugs of methyl
hydrogen fumarate and the benefits of such prodrugs. Gangakhedkar, 3–4.
Both Gangakhedkar and Sagi teach the use of carboxyl masking groups
including those which are structurally the same or similar. Compare,
Gangakhedkar, 63 (example 3 and 65, example 9) with Sagi, 28–29 (Table
A). It is prima facie obvious to substitute structurally similar compounds
where there is evidence that the compounds share similar properties. In re
Dillon, 919 F.2d 688, 691 (Fed. Cir. 1990). Given the teaching of the use of
the same or structurally similar prodrug moieties, we find that one skilled in
the art would have used the masking groups of Sagi for the compounds used
in the method of Gangakhedkar.
Appellants’ argument that the combination of Gangakhedkar and Sagi
would result in a structure different from what is claimed is also not
persuasive. Appellants offer no evidence, other than attorney argument, to
support their contention that combining monomethyl fumarate with the
prodrug moieties of Sagi would result in a peroxy-ester or per-ester. See,
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Appeal Br. 9. “Attorney’s argument in a brief cannot take the place of
evidence.” In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). As the
Examiner points out, the teachings of Gangakhedkar and Sagi support the
Examiner’s contention that the combination of the references would not lead
to the peroxy ester or per-ester structure advanced by Appellants but would
lead to the claimed structure. Ans. 14–19.
Appellants argue that neither of the references teach or suggest the
limitations regarding gastrointestinal irritation score, GST enzyme activity
or blood plasma concentration after dosing. Appeal Br. 10. Appellants
contend that the Examiner has improperly relied on inherency in that the
Examiner has failed to demonstrate that these properties necessarily flow
from the teachings of the art. Id.
Appellants’ argument is unpersuasive. The Examiner has
demonstrated that the combination of Gangakhedkar and Sagi would lead
one skilled in the art to create compounds falling within the scope of the
claims. As such one skilled in the art would expect the compounds to have
the same properties are recited in the claims absent evidence to the contrary.
In re Best, 562 F.2d 1252, 1255 (CCPA 1977). Here Appellants have
advanced no persuasive evidence showing that the prior art compounds
would not have the same properties as the claimed compounds.
Appellants contend that one skilled in the art would not have been
motivated to combine the teachings of Gangakhedkar and Sagi. Appeal Br.
11. Appellants contend that Gangakhedkar and Sagi teach the use of
structurally dissimilar core compounds and that there is no teaching or
suggestion in the references that would motivate one skilled in the art to
combine the teachings of the references. Id.
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Appellants contend that nothing in either reference suggests that the
disclosed prodrug moieties can be used for carboxylate groups generally and
absent such a teaching, there would be no motivation to combine the
references. Id. at 13. Appellants contend that Maag,6 cited by the Examiner
does not suggest that varied core drugs can use the same of similar prodrug-
moieties. Id.
We have considered Appellants arguments and remain unpersauded
that the rejection is in error. While we agree with Appellants that the core
compounds of Gangakhedkar and Sagi are dissimilar, both sets of
compounds are used to treat multiple sclerosis and both teach the use of
prodrug moieties. Gangakhedkar, 4; Sagi ¶ 225. As the Examiner notes,
both Gangakhedkar and Sagi teach the use of carboxylic acid prodrug
moieties and the importance to optimize them. Ans. 28. As discussed
above, Gangakhedkar and Sagi teach the use of the same or similar prodrug
moieties. These teachings in the references would lead one skilled in the art
to use the prodrug moieties of Sagi with the fumarate compounds of
Gangakhedkar. Id.
With respect to the teachings of Maag, while Maag teaches that only a
few carboxylic acid drugs have been evaluated and marketed, we do not find
that this teaches away from making the combination proposed by the
Examiner. As the Examiner points out:
It is well-known and understood that the number of compounds
that fail on the way to market significantly outstrips the number
of financially viable compounds. This is the reason that such a
high level of experimentation is expected and reasonable within

6 Hans Maag, Prodrugs of Carboxylic Acids, in Prodrugs, Challenges and
Rewards, Part 2 (Valention et al., eds., 2007) (“Maag”).
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the pharmaceutical arts. Further, both Gangakhedkar et al. and
Sagi et al. disclose dozens of differing promoieties for their
respective parent compounds, including overlapping moieties,
showcasing that it was not only well-known in the
pharmaceutical arts to try varied moieties to make prodrugs, it
was also well-known in relation to multiple sclerosis treatments
and was well-known with monomethyl fumarates.

Ans. 26.
Appellants contend that one skilled in the art would not have had a
reasonable expectation of success in creating the claimed compound
following the teachings of Gangakhedkar and Sagi. Appeal Br. 15.
Appellants contend that given the structural dissimilarities of the drug cores
of Gangakhedkar and Sagi and the lack of any teaching in Sagi that the
prodrug moieties could be used with other drug cores, one skilled in the art
would not expect the prodrug moieties of Sagi to work with the monomethyl
fumarate of Gangakhedkar. Id.
We are not persuaded by Appellants’ argument. “Obviousness does
not require absolute predictability of success. . . . For obviousness under
[section] 103, all that is required is a reasonable expectation of success.” In
re O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988).
We agree with the Examiner that Gangakhedkar and Sagi teach the
use of prodrug moieties to improve the effectiveness of carboxylic-acid-
based drugs. Ans. 16. As discussed above, Gangakhedkar and Sagi teach
the use of the same or structurally similar prodrug moieties. Compare,
Gangakhedkar, 63 (examples 3, 9 and 65) with Sagi, 28–29 (Table A).
From the discussion above, we find that the skilled artisan would have
been aware of both the disclosures of Gangakhedkar et al. and Sagi et al.,
and would have been aware that carboxylate-prodrugs were useful and
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known. We also find that the skilled artisan would have been aware that the
prodrug-moieties could be successfully substituted in the same drug-core,
and that the prodrug-moieties could be successfully used in differing drug-
cores. We agree with the Examiner that the skilled artisan would have
combined the teachings of using of carboxylate-promoieties and would have
done so with a reasonable expectation of success. Ans. 22.
Conclusion of Law
We conclude that a preponderance of the evidence supports the
Examiner’s conclusion that the subject matter of claim 1 would have been
obvious over Gangakhedkar combined with Sagi.
Claims 2, 11, 14–18, 20–22, 32, 36, and 37 have not been argued
separately and therefore fall with claim 1. See 37 C.F.R. § 41.37(c)(1)(iv).
SUMMARY
DECISION
We affirm the rejection for non-statutory obviousness-type double
patenting.
We affirm the rejection under 35 U.S.C. § 103(a).
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