Roshantha A. Chandraratna et al.

Patent Trials and Appeals Board

Aug 1, 2019

14507730 - (D) (P.T.A.B. Aug. 1, 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.
14/507,730 10/06/2014 Roshantha A. Chandraratna 1958481.00017 6642
45200 7590 08/01/2019
K&L Gates LLP-Orange County
1 Park Plaza
Twelfth Floor
IRVINE, CA 92614
EXAMINER
MATOS NEGRON, TAINA DEL MAR
ART UNIT PAPER NUMBER
1621
NOTIFICATION DATE DELIVERY MODE
08/01/2019 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):
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PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________________

Ex parte ROSHANTHA A. CHANDRARATNA,
ETHAN DMITROVSKY, ELIZABETH NOWAK,
RANDOLPH NOELLE, and MARTIN E. SANDERS1
____________________

Appeal 2018-002449
Application 14/507,730
Technology Center 1600
____________________

Before DEBORAH KATZ, TAWEN CHANG, and
JOHN E. SCHNEIDER, Administrative Patent Judges.

CHANG, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of treating a demyelination-related disorder, which have been
rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
STATEMENT OF THE CASE
Retinoid X receptors (RXRs) “function as ligand-activated nuclear
receptors which regulate the transcription of target genes.” (Spec. ¶ 10.)

1 Appellants identify the Real Party in Interest as Io Therapeutics, Inc.
(Appeal Br. 3.)
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The Specification teaches “administering a therapeutically effective amount
of a RXR agonist . . . to an individual suffering from an autoimmune
disorder, in particular a demyelination-related disorder.” (Id. ¶ 11.) The
Specification states that the disclosed RXR agonists can control the ratio of
T help cell Th17 and T regulatory (Treg) cells, which “may be crucial for the
stability of immune homeostasis,” as well as promote remyelination. (Id.
¶¶ 7, 11.)
Claims 1–4, 7–10, 14–21 are on appeal. Claims 1, 20, and 21 are the
only independent claims and are reproduced below:
1. A method of treating a demyelination-related
disorder, the method comprising the step of administering to an
individual in need thereof a therapeutically effective amount of
a selective RXR agonist with both remyelination promotion and
immunomodulatory activities, wherein administration of the
selective RXR agonist treats the demyelination-related disorder
in the individual by both promoting remyelination of neurons
and modulating the individual’s immune system, wherein the
selective RXR agonist is a compound having the structure of
formula XII:

wherein R is H, lower alkyl of 1 to 6 carbons, or a
pharmaceutically acceptable salt of the compound.

20. A method of treating multiple sclerosis, the
method comprising the step of administering to an individual in
need thereof a therapeutically effective amount of a selective
RXR agonist, wherein the selective RXR agonist is 3,7-
dimethyl-6(S), 7(S)-methano, 7-[1,1,4,4-tetramethyl-1,2,3,4-
Appeal 2018-002449
Application 14/507,730
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tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid;[2] and
wherein administration of the selective RXR agonist treats the
multiple sclerosis in the individual.

21. A method of treating a CNS demyelination-related
disorder, the method comprising the step of administering to an
individual in need thereof a therapeutically effective amount of
a selective RXR agonist, wherein the selective RXR agonist is
3,7-dimethyl-6(S),7(S)-methano, 7-[1,1,4,4-tetramethyl-1,2,3,4-
tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid; and wherein
administration of the selective RXR agonist treats the CNS
demyelination-related disorder in the individual and wherein
the selective RXR agonist is delivered directly to the CNS of
the individual by intrathecal administration, epidural
administration, cranial injection or implant, or nasal
administration.
(Appeal Br. 29, 31–32 (Claims App.).)
The Examiner rejects claims 1–4, 7–10, 14–17, 19, and 20 under pre-
AIA 35 U.S.C. § 103(a) as being unpatentable over Huang,3 Vuligonda,4
Kim,5 and Kimura.6 (Ans. 3.)

2 3,7-dimethyl-6(S), 7(S)-methano, 7-[1,1,4,4-tetramethyl-1,2,3,4-
tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid has the structure of
formula XII set forth in claim 1, wherein R is H. (Appeal Br. 29–30 (Claims
App.).)
3 Jeffrey K. Huang et al., Retinoid X Receptor Gamma Signaling Accelerates
CNS Remyelination, 14 NATURE NEUROSCIENCE 45–53 (2011).
4 Vuligonda et al., US Patent No. 5,917,082, issued June 29, 1999.
5 Ellen J. Kim et al., Immunopathogenesis and Therapy of Cutaneous T Cell
Lymphoma, in SCIENCE IN MEDICINE: THE JCI TEXTBOOK OF MOLECULAR
MEDICINE 156 (Marks and Neill eds. 2007). We note that the Examiner and
Appellants refer to this reference as “Marks” in the Final Action, Advisory
Action, Answer, and the briefs.
6 Akihiro Kimura et al., IL-6: Regulator of Treg/Th17 Balance, 40 Eur. J.
Immunology 1830–1835 (2010).
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The Examiner rejects claims 18 and 21 under pre-AIA 35 U.S.C.
§ 103(a) as being unpatentable over Huang, Vuligonda, Kim, Kimura, and
Jiang.7 (Ans. 9.)

DISCUSSION
Issue
The Examiner has rejected claims 1–4, 7–10, 14–17, 19, and 20 as
obvious over Huang, Vuligonda, Kim, and Kimura. The Examiner has
rejected claims 18 and 21 as obvious over Huang, Vuligonda, Kim, Kimura,
and Jiang. The same issue is dispositive for both rejections; we therefore
discuss them together.
The Examiner finds Huang suggests that RXR signaling contributes to
remyelination and further suggests retinoids8 as “potential drugs for
regenerative therapy in demyelinating disorder.” (Ans. 4.) The Examiner
finds that Huang does not explicitly teach the particular RXR agonist recited
in the claims. (Id. at 5.) However, the Examiner finds that Vuligonda
teaches the claimed compounds and further teaches that these compounds
have retinoid like biological activity, are highly specific agonists of RXR
retinoid receptor, and can be used to treat or prevent neurodegenerative
diseases. (Id.) The Examiner further finds that Kim teaches that

7 Jiang et al., US 2007/0185055 A1, published Aug. 9, 2007.
8 The Specification teaches that retinoids refer to ligands that activate the
retinoic acid receptors (RARs) while rexinoids refer to ligands that activate
the RXRs. (Spec. ¶ 8.) However, the Examiner and at least some of the
cited prior art appears to use the term retinoids more broadly to also include
ligands that activate the RXRs. (See, e.g., Jiang Abstract (describing
invention as relating to “the use of retinoid compounds that act on retinoid X
receptors (RXRs).”)
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“bexarotene[,] a retinoid X receptor-specific compound[,] has . . .
immunomodulatory effects,” while Kimura teaches that “normaliz[ing] the
balance between Th17 and Treg . . . may alleviate autoimmune symptoms.”
(Id. at 6.)
The Examiner concludes that a skilled artisan would have found it
obvious to use the compounds recited in the claims to treat multiple sclerosis
(i.e., a demyelination-related disorder) to arrive at the inventions of
independent claims 1 and 20, because Huang teaches selective RXR agonists
may be useful for treating multiple sclerosis while Vuligonda teaches that
the claimed compounds exhibit selective RXR agonist activity and is useful
for treatment of neurodegenerative diseases such as Parkinson’s disease and
inflammatory diseases. (Id. at 6–7.) The Examiner further concludes that
“[t]he skilled artisan would have been motivated to treat at least on[e]
symptom of multiple sclerosis such as inflammation because [Kim] taught
that administration of specific RXR agonist has immunomodulation
properties.” (Id. at 7.)
With respect to independent claim 21, which also requires that “the
selective RXR agonist [be] delivered directly to the CNS of the individual
by intrathecal administration, epidural administration, cranial injection or
implant, or nasal administration,” the Examiner further cites to Jiang as
teaching that the RXR agonist recited in claim 21 may be administered via
inhalation. (Id. at 9.)
Appellants contend that a skilled artisan would have no motivation to
substitute Vuligonda’s compounds for Huang’s rexinoids with a reasonable
expectation of success. (Appeal Br. 9–10, 11–12, 16–17.)
The issue with respect to the rejections is whether, in light of the cited
prior art, a skilled artisan would have had a reason to use the compounds of
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Vuligonda to treat a demyelination disorder, multiple sclerosis, or a CNS
demyelination-related disorder, as recited in the independent claims, with a
reasonable expectation of success.
Analysis
On balance, we find Appellants to have the better argument. In
particular, the Specification explains that RXRs can form homodimers as
well as heterodimers with other nuclear receptors. (Spec. ¶ 10; see also
Nishimaki-Mogami9 1007, left column; Ohsawa10 521, left column; Inoue11
Abstract; Lefebvre12 676, left column.) In response to the Examiner’s
rejection, Appellants have cited evidence that a skilled artisan would not
expect RXR agonists to have the same biological activity unless there is
evidence that they interact with the same receptor subset. (Appeal Br. 11, n.
11.)
Nishimaki-Mogami, for instance, describes the ability of two different
RXR agonists, PA024 and HX630, to activate the liver X receptor
(LXR)/retinoid X receptor (RXR) heterodimer and stimulate expression of
the ABC transporter A1 (ABCA1) protein. (Nishimaki-Mogami Abstract.)

9 Tomoko Nishimaki-Mogami, The RXR Agonists PA024 and HX630 Have
Different Abilities to Activate LXR/RXR and to Induce ABCA1 Expression in
Macrophage Cell Lines, 76 BIOLOGICAL PHARMACOLOGY 1006–1013
(2008).
10 Fuminori Ohsawa et al., Modification at the Lipophilic Domain of RXR
Agonists Differentially Influences Activation of RXR Heterodimers, 1 ACS
MEDICINAL CHEMISTRY LETTERS 521–525 (2010).
11 Makoto Inoue et al., Rexinoids Isolated from Sophora tonkinensis with a
Gene Expression Profile Distinct from the Synthetic Rexinoid Bexarotene,
77 J. OF NAT. PROD. 1670–1677 (2014).
12 Philippe Lefebvre et al., Retinoid X Receptors: Common
Heterodimerization Partners with Distinct Functions, 21 TRENDS IN
ENDOCRIN. & METAB. 676–683 (2010).
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Nishimaki-Mogami teaches that, in certain type of cells, both agonists
efficiently enhanced ABCA1 mRNA expression. (Id.) However, in other
types of cells, PA024 was highly effective while HX630 was inactive in
increasing ABCA1 mRNA. (Id.) Nishimaki-Mogami concludes that
“PA024 and HX630 have different abilities to activate LXR/RXR, and . . .
the cell-type-dependent effect of HX630 on ABCA1 expression . . . is
closely associated with this defect.” (Id.) Likewise, Ohsawa teaches that
“RXR permissive heterodimers are reported to be activated differently
depending upon the chemical structure of RXR agonists” and Inoue teaches
that two naturally occurring rexinoids possessed properties different from
synthetic rexinoid bexarotene. (Ohsawa Abstract; Inoue Abstract.) Finally,
Lefevbre teaches that “the structural diversity of rexinoids translates into
distinct pattern of gene expression induced upon treatment of target cells by
these molecules.” (Lefevbre 680, right column.)
In light of this evidence, which the Examiner has not persuasively
addressed, we agree with Appellants that the Examiner has not shown a
skilled artisan would have had reason to substitute, with a reasonable
expectation of success, the claimed RXR agonists disclosed in Vuligonda for
the RXR agonists that Huang suggests to be useful in treating multiple
sclerosis and/or demyelinating disorders.
We acknowledge the Examiner’s position that “the teachings of
Huang . . . in view of Vuligonda . . . would have provide[d] ample
motivation to exchange the selective RXR agonist since both compounds
exhibit selective RXR agonist activity and are useful for the treatment of
central nervous system diseases, inflammatory diseases and multiple
sclerosis.” (Ans. 15.) However, the Examiner concedes that Huang does
not teach the claimed RXR agonist. While Vuligonda does teach the
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claimed RXR agonists (compare compound in Vuligonda claim 1, with
compound in claim 1 on appeal), among others, and also teaches that uses
for its compounds include the prevention and treatment of “various
inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn’s
disease, neurodegenerative diseases such Alzheimer’s disease, Parkinson’s
disease and stroke, . . . [and] diseases associated with the immune system”
(Vuligonda 4:4–20), Vuligonda appears to suggest that the compounds of its
invention may be useful for treating the above conditions simply because of
their “retinoid-like activity” (see, e.g., id. at 2:1–17 (suggesting generally
that retinoid compounds are useful for preventing and/or treating, e.g.,
neurodegenerative diseases)).
In light of Appellants’ evidence that RXR receptor agonists do not all
have the same biological activity, we are not persuaded that Vuligonda’s
general statement regarding the usefulness of its compounds in preventing
and/or treating various diseases would provide a skilled artisan a reasonable
expectation that the claimed RXR agonist would be successful in treating a
demyelination-related disorder such as multiple sclerosis, even when
Vuligonda’s teaching is combined with the teaching in Huang and Kim that
certain other RXR agonists may be useful for treating multiple sclerosis and
demyelinating disorders and/or have immunomodulatory effects.
The Examiner also asserts that, since Huang describes “compounds
that have the same biomolecular activity/pathway (RXR agonist,
heterodimers 9RXR-gamma, alpha and beta), . . . there is no reason [not] to
believe that other RXR agonist could be used in the treatment of
demyelating disorders.” (Ans. 16–17.) We are not persuaded, because the
crux of Appellants’ argument and proffered evidence is that the effect of an
RXR agonist may depend on the particular heterodimeric partner to the
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retinoid X receptor (Reply Br. 4–5), and the Examiner has cited to no
evidence in the prior art that a skilled artisan would have reason to expect
that the claimed RXR agonist has the same ability to activate the relevant
RXR heterodimer as the agonists taught in Huang and/or Kim.
Accordingly, we reverse the Examiner’s rejection of independent
claims 1 and 20 as obvious over Huang, Vuligonda, Kim, and Kimura. We
likewise reverse the rejection of claims 2–4, 7–10, and 14–19, which depend
directly or indirectly from claim 1. In re Fine, 837 F.2d 1071, 1076 (Fed.
Cir. 1988) (“Dependent claims are nonobvious under section 103 if the
independent claims from which they depend are nonobvious.”). The
Examiner additionally cites Jiang in the rejection over independent claim 21,
but only for the teaching that the RXR agonist recited in claim 21 may be
administered via inhalation. (Ans. 9.) Thus, we reverse the Examiner’s
rejection of claim 21 for the same reasons.
SUMMARY
For the reasons above, we reverse the Examiner’s decision rejecting
claims 1–4, 7–10, and 14–21.

REVERSED