Chengzhi Zhang

Patent Trials and Appeals Board

Aug 21, 2019

14257347 - (D) (P.T.A.B. Aug. 21, 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.
14/257,347 04/21/2014 Chengzhi Zhang 102085.020526 7172
23377 7590 08/21/2019
BakerHostetler
Cira Centre 12th Floor
2929 Arch Street
Philadelphia, PA 19104-2891
EXAMINER
WEST, THEODORE R
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
08/21/2019 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):
eofficemonitor@bakerlaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte CHENGZHI ZHANG
__________

Appeal 2018-001199
Application 14/257,347
Technology Center 1600
__________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to
substituted aminopyrimidine compounds. The Examiner rejected the claims
as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We reverse.

1 Appellant identifies the Real Party in Interest as Teva Pharmaceutical
Industries Ltd. (See App. Br. 1).
2 We have considered and refer to the Specification of Apr. 21, 2014
(“Spec.”); Final Office Action of May 26, 2016 (“Final Action”); Appeal
Brief of Jan. 4, 2017 (“App. Br.”); Examiner’s Answer of Sept. 22, 2017
(“Ans.”); and Reply Brief of Nov. 15, 2017 (“Reply Br.”).
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Statement of the Case
Background
“Nilotinib . . . is a tyrosine kinase inhibitor. Nilotinib is commonly
prescribed for the treatment of chronic phase and accelerated phase
Philadelphia chromosome positive chronic myeloid leukemia” (Spec. ¶ 3).
However, “[n]ilotinib undergoes extensive oxidative metabolism via
CYP3A4, and to a lesser degree by CYP2C8, CYP2C9, and CYP2D6” (id.
¶ 4). These cytochrome enzymes “react with and convert [] foreign
substances to more polar intermediates or metabolites for renal excretion.
Such metabolic reactions frequently involve the oxidation of a carbon-
hydrogen (C-H) bond” (id. ¶ 5).
“Deuterium (2H or D) is a stable and non-radioactive isotope of
hydrogen” and “substituting a deuterium for [a] protium will cause a
decrease in the reaction rate” because “a C-D bond is stronger than the
corresponding C-1H bond” (id. ¶¶ 8–9). “Deuteration of pharmaceuticals to
improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity
profiles has been demonstrated previously with some classes of drugs” (id.
¶ 11). “[N]ilotinib is metabolized in humans at the imidazole and phenyl
methyl groups, the imidazole ring, and the trifluomethyl-bearing phenyl
ring. The current approach has the potential to prevent metabolism at these
sites” (id. ¶ 13).
The Claims
Claims 2, 4–6, 14, and 21–41 are on appeal. Claim 14 is the sole
independent claim and reads as follows:
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14. A compound that is

wherein at least one position designed as D as a deuterium
enrichment of no less than about 10%;
or a pharmaceutically acceptable salt thereof.

The Rejections
The Examiner rejected claims 2, 4–6, 14, 21–27, 32, and 34–41 under
35 U.S.C. § 103(a) as obvious over Manley,3 Breitenstein,4 Gant ’965,5 Gant
’622,6 Gant ’734,7 Gant ’026,8 Gant ’247,9 Gant ’316,10 Gant ’991,11 Gant
’886,12 Gant ’071,13 Gant ’200,14 Gant ’036,15 and Gant ’55516 (Ans. 2–4).

3 Manley et al., WO 2007/015871 A1, published Feb. 8, 2007.
4 Breitenstein et al., WO 2004/005281 A1, published Jan. 15, 2004.
5 Gant et al., US 2007/0281965 A1, published Dec. 6, 2007.
6 Gant et al., US 2007/0149622 A1, published June 28, 2007.
7 Gant et al., US 2007/0287734 A1, published Dec. 13, 2007.
8 Gant et al., US 2008/0319026 A1, published Dec. 25, 2008.
9 Gant et al., US 2008/0312247 A1, published Dec. 18, 2008.
10 Gant et al., US 2008/0300316 A1, published Dec. 4, 2008.
11 Gant et al., US 2008/0280991 A1, published Nov. 13, 2008.
12 Gant et al., US 2008/0280886 A1, published Nov. 13, 2008.
13 Gant et al., US 2008/0268071 A1, published Oct. 30, 2008.
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The Examiner rejected claims 14, 22, 24, 25, 28–31, and 33 under
35 U.S.C. § 103(a) as obvious over Manley, Breitenstein, Gant, and Lewis17
(Ans. 5–6).
The Examiner finds Manley teaches “the hydrochloride monohydrate
salt of the compound of Formula I” (Final Act. 4). The Examiner finds
Breitenstein teaches “the compound of Formula I” and “discloses methods
of treating tyrosine kinase-mediated disorders (pp. 32-33), such as
Philadelphia-positive chronic myelogenous leukemia” (id.).
The Examiner acknowledges “these references do not specifically
disclose the deuterium-enriched compounds of Formula I” (Final Act. 4).
The Examiner finds Gant18 teaches “deuterium-enriched zolpidem,
venlafaxine, rimonabant, pirfenidone, ranolazine, phenylephrine,
agomelatine, pimavanserin, ketamine, ilaprazole, sitaxsentan, and losartan”
(Final Act. 4).
The Examiner finds “one skilled in the art would have been motivated
to deuterate the compound of either Manley et al. or Breitenstein et al. in
order to take advantage of improvements in pharmacological properties that
deuterium substitution affords” (Final Act. 5).

14 Gant et al., US 2008/0255200 A1, published Oct. 16, 2008.
15 Gant et al., US 2008/0255036 A1, published Oct. 16, 2008.
16 Gant et al., US 2008/0132555 A1, published June 5, 2008.
17 Lewis et al., WO 2004/103344 A1, published Dec. 2, 2004.
18 Because only specific citation by paragraph in the rejection is to the Gant
’555 publication, we will limit our review to that publication. See 37 C.F.R.
§ 1.104(c)(2) (“[T]he particular part [of the prior art] relied on must be
designated as nearly as practicable.”)
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The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that the prior art
suggests the claimed compound?
Findings of Fact
1. Manley teaches “protein kinase inhibitor useful in therapy for
diseases which respond to inhibition of protein kinase activity” (Manley
¶ 2).
2. Manley teaches preparation of the monohydrochloride
monohydrate salt of a kinase inhibitor as shown below:

Manley teaches a process “to obtain 4-methyl-N-[3-(4-methyl-imidazol-1-
yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-
benzamide monohydrochloride monohydrate salt” (Manley ¶¶ 34–35).
3. Breitenstein teaches “a method for the treatment of leukaemia
which responds to an inhibition of the Abl tyrosine kinase activity, which
comprises administering a compound of formula I or a N-oxide or a
pharmaceutically acceptable salt thereof” (Breitenstein 32).
4. Breitenstein teaches a process of making “4-Methyl-3-[[4-(3-
pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-
(trifluoromethyl)phenyllbenzamide” (Breitenstein 63).
5. Gant ’555 teaches:
The deuterated analogs of this invention have the potential to
uniquely maintain the beneficial aspects of the non-isotopically
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enriched drugs while substantially increasing the half-life (T1/2),
lowering the maximum plasma concentration (Cmax) of the
minimum efficacious dose (MED), lowering the efficacious
dose and thus decreasing the non-mechanism-related toxicity,
and/or lowering the probability of drug-drug interactions.
(Gant ’555 ¶ 90).
6. Gant ’555 teaches compounds that have properties including:
a) decreased inter-individual variation in plasma levels of said
compound or a metabolite thereof as compared to the non-
isotopically enriched compound; b) increased average plasma
levels of said compound per dosage unit thereof as compared to
the nonisotopically enriched compound; c) decreased average
plasma levels of at least one metabolite of said compound per
dosage unit thereof as compared to the non-isotopically
enriched compound; d) increased average plasma levels of at
least one metabolite of said compound per dosage unit thereof
as compared to the non-isotopically enriched compound; and e)
an improved clinical effect during the treatment in said subject
per dosage unit thereof as compared to the non-isotopically
enriched compound. In yet further embodiments said
compound has at least two of the following properties: a)
decreased inter-individual variation in plasma levels of said
compound or a metabolite thereof as compared to the non-
isotopically enriched compound; b) increased average plasma
levels of said compound per dosage unit thereof as compared to
the nonisotopically enriched compound; c) decreased average
plasma levels of at least one metabolite of said compound per
dosage unit thereof as compared to the non-isotopically
enriched compound; and d) increased average plasma levels of
at least one metabolite of said compound per dosage unit
thereof as compared to the non-isotopically enriched
compound; and e) an improved clinical effect during the
treatment in said subject per dosage unit thereof as compared to
the non-isotopically enriched compound. In yet further
embodiments said compound has a decreased metabolism by at
least one polymorphically-expressed cytochrome P450 isoform
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in said subject per dosage unit thereof as compared to the non-
isotopically enriched compound.
(Gant ’555 ¶¶ 27–39; paragraph numbers omitted).
7. Gant teaches “deuterium incorporation can lead to metabolic
switching” and “[m]etabolic switching can potentially lead to different
proportions of known metabolites as well as altogether new metabolites.
This new metabolic profile may impart more or less toxicity. Such pitfalls
are non-obvious and are not predictable a priori for any drug class” (Gant
’555 ¶ 87).
Principles of Law
Under the lead compound analysis rubric, we must first “determine[]
whether a chemist of ordinary skill would have selected the asserted prior art
compounds as lead compounds, or starting points, for further development
efforts.” Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir.
2012). “The second inquiry in the analysis is whether the prior art would
have supplied one of ordinary skill in the art with a reason or motivation to
modify a lead compound to make the claimed compound with a reasonable
expectation of success.” Id. at 1292.
A prima facie case for obviousness requires “a reason that would have
prompted a person of ordinary skill in the relevant field to combine the
elements in the way the claimed new invention does.” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 418 (2007).
Analysis
Appellant contends the “Examiner has failed to articulate a single
reason why one of ordinary skill in the art would have deuterated any of
Breitenstein’s or Manley’s compounds” (App. Br. 5). Appellant contends
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the “cited art does not disclose or suggest that nilotinib could benefit from
chemical modification. Significantly, neither reference suggests that
nilotinib possesses any metabolic or other pharmacokinetic deficiencies”
(App. Br. 6). Appellant also contends the “Examiner provides no rationale
as to why the person of ordinary skill in the art would have selected the
particular C-1H bonds for substitution with C-2H bonds, to arrive at the
particular d3 analogue claimed” (App. Br. 7). Lastly, Appellant provides a
number of disclosures showing “the unpredictable consequences of
deuteration” (App. Br. 9–12) including that “Nevirapine deuteration resulted
in increased metabolism, rather than decreased metabolism” (App. Br. 12).
The Examiner states, in the context of substituting equivalents that
“there is no requirement that the examiner must provide a specific rationale
to select one compound over another” (Ans. 7). The Examiner states that “it
is the examiner’s position that deuteration of nilotinib is prima facie obvious
per se. On the other hand, figuring out which of the 22 hydrogen atoms to
substitute for deuterium would have been a matter of routine
experimentation” (Ans. 8). The Examiner also states that the Gant
references “would have provided motivation to the skilled artisan to make
deuterium-substituted nilotinib in order to take advantage of the favorable
properties that this modification would be expected to produce” (Ans. 9).
We agree with Appellant. The Examiner is incorrect on the legal
standard for obviousness because “rejections on obviousness grounds cannot
be sustained by mere conclusory statements; instead, there must be some
articulated reasoning with some rational underpinning to support the legal
conclusion of obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006).
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Whether in the context of substituting known equivalents or in
providing motivation, the burden is on the Examiner to establish a prima
facie case. There is no such thing as “prima facie obvious per se.” We do
not disagree that express reasons for substituting equivalents need not be
present, but “[i]n order to rely on equivalence as a rationale supporting an
obviousness rejection, the equivalency must be recognized in the prior art,
and cannot be based on applicant’s disclosure or the mere fact that the
components at issue are functional or mechanical equivalents.” MPEP
§ 2144.06(II). The Examiner has not provided any evidence that any of the
deuterated compounds of Gant are functionally equivalent to the specific
compound of claim 14 nor has the Examiner provided any evidence of any
structural similarity.
If we apply the lead compound analysis, we might agree with the
Examiner that nilotinib is a reasonable lead compound based on the
teachings of Manley and Breitenstein (FF 1–4) and that Gant provides
several generic reasons to modify nilotinib by deuteration (FF 5–6).
However, claim 14 is not a generic modification of nilotinib by deuteration
but rather is a modification of a particular position on the molecule. The
Examiner provides no reason to make the particular modification required.
In contrast, Appellant has provided a number of disclosures
demonstrating that deuteration of different chemicals yields unpredictable
results19 (see App. Br. 9–12), consistent with the disclosure in the
Specification that deuteration may yield a “new metabolic profile [that] may
impart more or less toxicity. Such pitfalls are non-obvious and are not

19 We recognize that the Specification lacks any working examples, but the
current rejection is for obviousness, not enablement.
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predictable a priori for any drug class” (Spec. ¶ 11). Gant ’555 provides a
similar disclosure, teaching that “deuterium incorporation can lead to
metabolic switching” and “[m]etabolic switching can potentially lead to
different proportions of known metabolites as well as altogether new
metabolites. This new metabolic profile may impart more or less toxicity.
Such pitfalls are non-obvious and are not predictable a priori for any drug
class” (FF 7).
While O’Farrell states that “[o]bviousness does not require absolute
predictability of success,” O’Farrell identifies
two kinds of error. In some cases, what would have been
“obvious to try” would have been to vary all parameters or try
each of numerous possible choices until one possibly arrived at
a successful result, where the prior art gave either no indication
of which parameters were critical or no direction as to which of
many possible choices is likely to be successful. In others,
what was “obvious to try” was to explore a new technology or
general approach that seemed to be a promising field of
experimentation, where the prior art gave only general guidance
as to the particular form of the claimed invention or how to
achieve it.
In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988) (citations omitted). The
instant situation fits O’Farrell’s second kind of error, since the prior art of
Gant ’555 at best provides general guidance that deuteration of molecules
may sometimes improve their properties (FF 5–6). While deuteration might
represent a promising field of experimentation, Gant ’555 itself
demonstrates that the results of deuteration are not predictable (FF 7). There
is also no persuasive evidence that the experimentation required to identify a
deuterated nilotinib would have been merely routine as asserted by the
Examiner (see Ans. 8).
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Therefore, because the Examiner provides no reason or evidence to
deuterate the particular position of nilotinib required by claim 14 and
because the Specification and Gant ’555 evidence the unpredictability of
deuteration, we find the evidence does not support a finding of a reasonable
expectation of success.
Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner’s conclusion that the prior art suggests the claimed compound.

SUMMARY
In summary, we reverse the obviousness rejections.

REVERSED