Thomas G. Gant et al.

Patent Trials and Appeals Board

Jul 18, 2019

15597733 - (D) (P.T.A.B. Jul. 18, 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.
15/597,733 05/17/2017 Thomas G. Gant 102085021317/
AUSP002-D-US
1842
46347 7590 07/18/2019
BakerHostetler
Cira Centre, 12th Floor
2929 Arch Street
Philadelphia, PA 19104-2891
EXAMINER
DESAI, RITA J
ART UNIT PAPER NUMBER
1625
NOTIFICATION DATE DELIVERY MODE
07/18/2019 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 THOMAS G. GANT, MANOUCHEHR SHAHBAZ,
and CHENGZHI ZHANG1
__________

Appeal 2019-002173
Application 15/597,733
Technology Center 1600
__________

Before ERIC B. GRIMES, FRANCISCO C. PRATS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
pharmaceutical formulation, which have been rejected for obviousness and
obviousness-type double patenting. We have jurisdiction under 35 U.S.C.
§ 6(b).
We affirm but designate the affirmance a new ground of rejection.

1 Appellants state that “[t]he assignee of this application is Auspex
Pharmaceuticals, Inc. Teva Pharmaceutical Industries Ltd. acquired Auspex
in 2015.” Appeal Br. 1.
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STATEMENT OF THE CASE
Dihydrotetrabenazine has the following chemical structure:

Spec. ¶ 3. “Dihydrotetrabenazine is an active metabolite of tetrabenazine,
which is currently used for the treatment of Huntington’s disease.” Id.
“Dihydrotetrabenazine is currently under investigation for the treatment of
Huntington’s disease” and other disorders. Id.
“Deuteration of pharmaceuticals to improve pharmacokinetics (PK),
pharmacodynamics (PD), and toxicity profiles has been demonstrated
previously with some classes of drugs.” Id. ¶ 11. “Increased levels of
deuterium incorporation . . . could effect [sic] the pharmacokinetic,
pharmacologic and/or toxicologic profiles of [] dihydrotetrabenazine.” Id.
¶ 12. “The deuteration approach has the strong potential to slow the
metabolism of dihydrotetrabenazine and attenuate interpatient variability.”
Id. ¶ 13.
Claims 1, 3–6, and 8–25 are on appeal. Claim 1 is representative and
reads as follows:
1. A long acting pharmaceutical formulation comprising a
therapeutically effective amount of a compound of Formula

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or a salt or stereoisomer thereof,
wherein each position represented as D has deuterium enrichment of
no less than about 10%; and
a polymeric material, a hydrophobic material, or an ion exchange
resin;
wherein the long acting pharmaceutical formulation is in the form of a
depot preparation.

The claims stand rejected as follows:
Claims 1, 3–6, and 8–25 under 35 U.S.C. § 103(a) as obvious based
on Clarke,2 Foster (1984),3 Foster ’325,4 Gant ’981,5 and Tridgett6 (Ans. 37);
and
Claims 1, 3–6, and 8–25 for obviousness-type double patenting based
on claims 1–3 of U.S. Patent 8,524,733 in view of Clarke and Gant ’981
(Ans. 88).

2 Clarke et al., WO 2005/077946 A1, published Aug. 25, 2005.
3 Allan B. Foster, Deuterium isotope effects in studies of drug metabolism,
TIPS, Dec. 1984, pp. 524–527.
4 Foster et al., WO 95/26325, published Oct. 5, 1995.
5 Gant et al., WO 2010/044981 A2, published Apr. 22, 2010.
6 Tridgett et al., WO 2007/007105 A1, published Jan. 18, 2007.
7 The statement of the rejection also includes Duffield et al., US
2012/0208773 A1 (Aug. 16, 2012), and Gant et al., WO 2007/139923 A1
(Dec. 6, 2007). However, these references are not mentioned in the body of
the rejection, and therefore they do not appear to be part of the evidence
relied on to show that the claimed invention would have been obvious.
8 The statement of the rejection also includes Tridgett and Gant ’923.
However, these references are not mentioned in the body of the rejection,
and therefore they do not appear to be part of the evidence relied on to show
that the instant claims define an obvious variant of the claims of the ’733
patent.
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I
The Examiner has rejected claims 1, 3–6, and 8–25 under 35 U.S.C.
§ 103(a) as obvious based on Clarke, Foster (1984), Foster ’325, Gant ’981,
and Tridgett. Ans. 3. The Examiner finds that the references disclose each of
the elements of the claimed formulation—dihydrotetrabenazine and
pharmaceutical formulations thereof, deuteration, and depot preparations—
and concludes that it would have been obvious to combine them in the
manner required by claim 1. Id. at 3–6.
We agree that the formulation of claim 1 would have been obvious
based on Gant ’981 and Clarke. Our fact-finding and reasoning differ from
those of the Examiner, however, and for that reason we designate our
affirmance a new ground of rejection in order to allow Appellants a fair
opportunity to respond.
Gant ’981 discloses that “[t]etrabenazine is commonly prescribed for
the treatment of Huntington’s disease.” Gant ’981 ¶ 3. “In vivo,
tetrabenazine is rapidly and extensively metabolized to its reduced form.”
Id. ¶ 4. Clarke confirms that “[t]etrabenazine . . . is extensively metabolised
by first-pass metabolism.” Clarke 3:3–4. “The major metabolite is
dihydrotetrabenazine . . . which is formed by reduction of the 2-keto group
in tetrabenazine, and is believed to be primarily responsible for the activity
of the drug.” Id. at 3:5–8.
Gant ’981 discloses that “[i]ncreased levels of deuterium
incorporation may . . . affect the pharmacokinetic, pharmacologic and/or
toxicologic profiles of tetrabenazine.” Gant ’981 ¶ 12. “Various deuteration
patterns can be used to (a) reduce or eliminate unwanted metabolites, (b)
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increase the half-life of the parent drug,” etc. Id. ¶ 13. “[A] medicine with a
longer half-life may result in greater efficacy and cost savings.” Id. Gant
’981 discloses that “[t]he deuteration approach has the strong potential to
slow the metabolism of tetrabenazine and attenuate interpatient variability.”
Id.
Gant ’981 exemplifies synthesis of d6-tetrabenazine, which has the
following structure:

Id. ¶ 104. Gant ’981 states that “the symbol ‘D’, when used to represent a
given position in a drawing of a molecular structure, means that the specified
position is enriched with deuterium. . . . In one embodiment deuterium
enrichment is . . . no less than about 10%.” Id. ¶ 27.
Gant ’981 states that “[c]hanges in the metabolic properties of the
compounds disclosed herein as compared to their non-isotopically enriched
analogs can be shown using [specified] assays.” Id. ¶ 110. Gant ’981 describes
an “[I]n Vitro Liver Microsomal Stability Assay,” and states that “[i]t has thus
been found that certain deuterium-enriched compounds disclosed herein that
have been tested in this assay showed an increased degradation half-life as
compared to the non-isotopically enriched drug. The degradation half-lives of
Examples 1 and 2 (tetrabenazine and d6-tetrabenazine) are shown in Table 1.”
Id. The table shows that tetrabenazine and d6-tetrabenazine (Examples 1 and
2, respectively) have a “% increase of HLM [human liver microsomal]
degradation half-life” of “-30% - 0%” and “0% - 30%,” respectively. Id.
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Gant ’981 discloses pharmaceutical compositions comprising its
compounds. Id. ¶ 52. “The compositions include those suitable for oral,
parenteral . . . , intraperitoneal, transmucosal, transdermal, rectal and topical
. . . administration.” Id. ¶ 53. “In addition to the formulations described
previously, the compounds may also be formulated as a depot preparation.”
Id. ¶ 58. “[T]he compounds may be formulated with suitable polymeric or
hydrophobic materials (for example as an emulsion in an acceptable oil) or
ion exchange resins.” Id.
Clarke states that “tetrabenazine is currently used for treating
hyperkinetic movement disorders such as Huntington’s disease.” Clarke 1:8–
10. Clarke states that “[t]etrabenazine exerts its therapeutic effects by
inhibiting the vesicular monoamine transporter VMAT2 in the brain and by
inhibiting both pre-synaptic and post-synaptic dopamine receptors.” Id. at
18:12–14. Clarke discloses “dihydrotetrabenazine isomers . . . [that] are also
inhibitors of VMAT2.” Id. at 18:15–16. Clarke discloses that its
dihydrotetrabenazine compounds are useful for treating Huntington’s
disease. Id. at 19:15–16.
Clarke discloses that its “dihydrotetrabenazine isomers . . . are not
only stable but have unexpectedly good biological properties.” Id. at 4:18–
20. Specifically, “several of the isomers . . . show greatly reduced or
negligible binding of dopamine receptors indicating that they are unlikely to
give rise to the dopaminergic side effects encountered with tetrabenazine.”
Id. at 4:22–25. “[S]tudies in rats on several of the isomers have shown that
they lack the unwanted sedative side effects associated with tetrabenazine.”
Id. at 4:26–28. Clarke discloses pharmaceutical compositions comprising
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dihydrotetrabenazine, in a form suitable for various routes of administration.
Id. at 20:12–16.
The formulation of claim 1 on appeal would have been obvious to a
person of ordinary skill in the art based on the above teachings. Specifically,
Gant ’981 disclose a deuterated compound that is identical to the compound
recited in claim 1 except that the compound of Gant ’981 is derived from
tetrabenazine and the compound of claim 1 is derived from dihydro-
tetrabenazine. The two compounds are shown below for comparison:
Compound of Gant ’981 Compound of Claim 1

Gant ’981 and Clarke disclose that both compounds are useful for
treating Huntington’s Disease. Gant ’981 suggests formulating its
compounds with polymeric or hydrophobic materials or ion exchange resins
as a depot preparation. Based on this express suggestion, it would have been
obvious to formulate Clarke’s dihydrotetrabenazine compounds with
polymeric or hydrophobic materials or ion exchange resins as a depot
preparation, because Clarke discloses that dihydrotetrabenazine is the major
metabolite of tetrabenazine and primarily responsible for its activity.
Thus, a skilled artisan would have recognized that Clarke’s
dihydrotetrabenazine and the compounds of Gant ’981 are functionally
equivalent, and therefore obvious to substitute. See In re Omeprazole Patent
Litigation, 483 F.3d 1364, 1374 (Fed. Cir. 2007) (“[T]his court finds no . . .
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error in [the] conclusion that it would have been obvious to one skilled in the
art to substitute one ARC [alkaline reactive compound] for another.”).
Further reason to substitute Clarke’s dihydrotetrabenazine for the
tetrabenazine of Gant ’981 is provided by Clarke, which teaches that its
compounds do not bind dopamine receptors, suggesting that they are
unlikely to cause tetrabenazine’s dopaminergic (sedative) side effects.
In addition, it would have been obvious to modify Clarke’s
dihydrotetrabenazine by deuterating it, because Gant ’981 teaches that
deuteration can, among other things, reduce unwanted metabolites and
increase the half-life of a drug. It would have been obvious to specifically
deuterate the methoxy groups (i.e., changing the -OCH3 groups to -OCD3
groups) of Clarke’s dihydrotetrabenazine because Gant ’981 exemplifies
(Example 2) a deuterated tetrabenazine with deuterated methoxy groups.
Gant ’981 specifically states that “[t]he deuteration approach has a
strong potential to slow the metabolism of tetrabenazine and attenuate
interpatient variability.” Gant ’981 ¶ 13. This disclosure is sufficient to
provide the skilled artisan with a reasonable expectation that deuteration of
dihydrotetrabenazine, which is closely related both structurally and
functionally to tetrabenazine, would also be likely to slow its metabolism
and attenuate interpatient variability.
In summary, Gant ’981 and Clarke provide sufficient reasons for a
person of ordinary skill in the art to deuterate dihydrotetrabenazine, in the
manner recited in claim 1, and to formulate it as a depot preparation,
resulting in the claimed formulation. Claim 1 is therefore unpatentable under
35 U.S.C. § 103(a) over Gant ’981 and Clarke.
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Appellants argue that “[d]euterium substitution . . . requires
significant trial and error, with no guarantee of successfully producing a
drug having an improved metabolic profile.” Appeal Br. 5. Appellants cite
several references as evidence of “the unpredictability of the deuterium
isotope effect.” Id. at 5–9.
Appellants state that “[t]he summarized references are of record in
this application’s parent, U.S. Application No. 14/820,176, and is deemed to
have been considered by the Examiner in this continuing application. See,
e.g. MPEP 609.02.” Id. at 5, n. 8. The fact that evidence submitted in a
related application is deemed to be considered by the examiner, however,
does not necessarily mean it is properly relied on in an appeal. An Appeal
Brief must contain “[t]he arguments of appellant with respect to each ground
of rejection, and the basis therefor, with citations of the statutes, regulations,
authorities, and parts of the Record relied on.” 37 C.F.R. § 41.37(c)(1)(iv)
(emphasis added). The newly-cited references are not part of the record of
this application and we decline to comb the record of a different application
in order to find them.
In any event, we find Appellants’ characterizations of the references,
assuming for present purposes they are accurate, do not show that a skilled
artisan would have lacked a reasonable expectation of success in deuterating
dihydrotetrabenazine to form the compound recited in claim 1, because Gant
’981 exemplifies a tetrabenazine compound with the identical deuteration
pattern and states that “[t]he deuteration approach has a strong potential to
slow the metabolism of tetrabenazine and attenuate interpatient variability.”
Gant ’981 ¶ 13.
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Deuterated dihydrotetrabenazine and deuterated tetrabenazine (e.g.,
Example 2 in Gant ’981) are closely related structurally and functionally.
Thus, a skilled artisan would have reasonably expected that the prediction of
Gant ’981 would also apply to deuterated dihydrotetrabenazine. The
compounds of the references cited by Appellants, on the other hand, are
much less closely related in structure to dihydrotetrabenazine than
tetrabenazine is. And Appellants do not characterize any of the cited
compounds as inhibitors of VMAT2, like both dihydrotetrabenazine and
tetrabenazine. We therefore conclude that the evidence cited by Appellants,
even assuming it is accurately summarized in the Appeal Brief, is inadequate
to outweigh the expectation of success provided by Gant ’981.
Appellants also argue that, “even if one of ordinary skill in the art had
prepared a deuterated dihydrotetrabenazine analog for human administration –
a point the Appellant does not concede – the cited art is devoid of any
suggestion that a deuterated dihydrotetrabenazine analog should be formulated
as a long-acting implant or injection.” Appeal Br. 10. That is, “having
achieved [a] ‘longer lasting effect’ with a deuterated analog, the Examiner has
not explained what would have then motivated the skilled person to again
extend the duration of action of a compound that already should have had an
extended duration of action.” Id. (quoting Final Action 7).
This argument is also unpersuasive. Gant ’981 discloses that
deuteration can be used to increase the half-life of a drug; that deuterating
tetrabenazine has the “strong potential” to slow its metabolism; and that “a
medicine with a longer half-life may result in greater efficacy and cost
savings.” Gant ’981 ¶ 13. Gant ’981 also expressly suggests formulating its
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compounds as a depot preparation to produce “long acting formulations.”
Id. ¶ 58. Gant ’981 thus suggests both deuteration and depot formulations for
its tetrabenazine-derived compounds, which would have reasonably led a
skilled artisan to apply both suggestions to Clarke’s dihydrotetrabenazine
compounds.
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) based on Gant ’981 and Clarke. Claims 3–6 and 8–25 fall with
claim 1 because they were not argued separately. 37 C.F.R.
§ 41.37(c)(1)(iv).
II
The Examiner has rejected claims 1, 3–6, and 8–25 for obviousness-
type double patenting based on claims 1–3 of U.S. Patent 8,524,733 in view
of Clarke and Gant ’981. The Examiner reasons that “the claims of the
[’733] patent are drawn to deuterated form of tetrabenazine and its
pharmaceutical composition,” and are not patentably distinct from the
instant claims because
Clarke et al. teaches that dihydrotetrabenazine is the metabolite
primarily responsible for the activity. Gant [’981] teaches the
tetrabenazine in depot formulations. Therefore one of skill in
the art would be motivated to make the formulations of the
deuterated dihydrotetrabenazine. The rejection is made upon
obviousness and the above references teach the depot
preparations, e.g. Gant [’981].
Ans. 8.
We agree that deuterated dihydrotetrabenazine, in a depot
formulation, would have been an obvious variation of the deuterated
tetrabenazine claimed in the ’733 patent in view of the teachings of Gant
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’981 and Clarke, for the reasons discussed above with respect to
obviousness.
Appellants argue that “[t]he claims of the 733 patent are directed to,
e.g., d6-tetrabenazine” and, “[a]s discussed above, the claims are non-
obvious over the subject matter claimed in the ‘733 patent.” Appeal Br. 13.
For the reasons discussed above, however, we conclude that the
claimed formulation would have been an obvious variant of the d6-
tetrabenazine claimed in the ’733 patent, which is the same compound as in
Example 2 in Gant ’981, based on the teachings of Gant ’981 and Clarke.
We therefore affirm the rejection of claims 1, 3–6, and 8–25 for
obviousness-type double patenting based on claims 1–3 of U.S. Patent
8,524,733 in view of Clarke and Gant ’981.
SUMMARY
We affirm both of the rejections on appeal, but we designate the
affirmances as new grounds of rejection in order to give Appellants a fair
opportunity to address them. See In re Kronig, 539 F.2d 1300, 1302–03
(CCPA 1976).
TIME PERIOD FOR RESPONSE
This decision contains new grounds of rejection pursuant to 37 C.F.R.
§ 41.50(b). Section 41.50(b) provides “[a] new ground of rejection pursuant
to this paragraph shall not be considered final for judicial review.” Section
41.50(b) also provides:
When the Board enters such a non-final 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
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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 § 41.52 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 Manual of Patent Examining Procedure § 1214.01.

37 C.F.R. § 41.50(b)