TECHFIELDS PHARMA CO., LTD.

Patent Trials and Appeals Board

Feb 11, 2020

14542486 - (D) (P.T.A.B. Feb. 11, 2020)

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.
14/542,486 11/14/2014 Chongxi YU 12799.0024-00000 7458
7590 02/11/2020
Techfields Pharma Co., Ltd.
2358 Chang'an Road, Building #14, Wujiang District
Suzhou, Jiangsu, 215200
CHINA
EXAMINER
RODRIGUEZ, RAYNA B
ART UNIT PAPER NUMBER
1628
MAIL DATE DELIVERY MODE
02/11/2020 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte CHONGXI YU and LINA XU 1
Appeal 2019-001126
Application 14/542,486
Technology Center 1600
Before ERIC B. GRIMES, DEBORAH KATZ, and,
MICHAEL A. VALEK, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
pharmaceutical composition, which have been rejected as obvious and as
containing an improper Markush group. We have jurisdiction under
35 U.S.C. § 6(b).
We AFFIRM.

1 Appellant identifies the real party in interest as TECHFIELDS PHARMA
CO., LTD. Appeal Br. 3. We use the word Appellant to refer to “applicant”
as defined in 37 C.F.R. § 1.42(a).
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Application 14/542,486

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STATEMENT OF THE CASE
The “invention relates to the field of pharmaceutical compositions
capable of penetrating one or more biological barriers.” Spec. ¶ 2. “One
aspect of the invention is directed to a high penetration prodrug (HPP) or a
high penetration composition (HPC).” Id. ¶ 5. “HPP” or “HPC” refer to “a
composition comprising a functional unit covalently linked to a
transportational unit through a linker.” Id.
“In certain embodiments, a parent drug of an HPP or HPC is a drug
that can be used by itself or in combination with other drug(s) to treat
pulmonary conditions.” Id. ¶¶ 9, 10. Exemplary parent drugs include “5-
lipoxygenase inhibitors includ[ing] . . . zileuton [(RS)-N-[1-(1-benzothien-2-
yl)ethyl]-N-hydroxyurea].” Id. ¶ 12.
Claims 19, 51, 54, 57, and 60 are on appeal. Claim 19 is the only
independent claim and is directed to “[a] pharmaceutical composition
comprising a pharmaceutically acceptable carrier and one or more
compounds selected from a compound of Structure LRA-1 and a compound
of Structure 5-LI-1,” where Structure LRA-1 and Structure 5-LI-1 are
defined by chemical formulas with variable positions that are selected from
certain substituents. Appeal Br. 26–30 (Claims Appendix). In response to an
election of species requirement, Appellant elected the species of (RS)-N-[1-
(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxy)urea hydrochloride,
with the following structure:
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wherein HA is HCl. Response to Election/Restriction filed March 18, 2016,
page 2. The elected species is within the genus defined by Structure 5-LI-1
recited in claim 19.
The claims stand rejected as follows:
Claim 19 on the ground of containing an improper Markush group
(Ans. 3) and
Claims 19, 51, 54, 57, and 60 under 35 U.S.C. § 103(a) as obvious
based on Trivedi,2 Järvinen,3 Mahfouz,4 and Walson5 (Ans. 7).

2 Jay S. Trivedi, Solubility and stability characterization of zileuton in a
ternary solvent system, European Journal of Pharmaceutical Sciences 4:109–
116 (1996).
3 Tomi Järvinen, Design and Pharmaceutical Applications of Prodrugs, in
Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development, and
Manufacturing, Shayne C. Gad (ed.), John Wiley & Sons, pp. 1–64 (2010).
4 Nadia M. Mahfouz, Synthesis, chemical and enzymatic hydrolysis, and
bioavailability evaluation in rabbits of metronidazole amino acid ester
prodrugs with enhanced water solubility, Journal of Pharmacy and
Pharmacology 53:841–848 (2001).
5 Philip D. Walson, Antipyretic Efficacy and Tolerability of a Single
Intravenous Dose of the Acetaminophen Prodrug Propacetamol in Children:
A Randomized, Double-Blind, Placebo-Controlled Trial, Clinical
Therapeutics 28:762–796 (2006).
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OPINION
Improper Markush Group
Claim 19 stands rejected on the ground of containing an improper
Markush group, because the Examiner finds that the compounds of Structure
5-LI-1 do not share a single structure similarity with the compounds of
Structure LRA-1. Ans. 3–5. Specifically, the Examiner finds:
Compounds of Structure LRA-1 are quinoline class compounds
that would be classified under class 546, subclass 112.
Compounds of Structure 5-LI-1 are benzothiophene class
compounds that would be classified under class 532, subclass
49. These compounds lack unity of invention since they: do not
share a common utility and/or they do not share a substantial
structural feature essential to that utility.
Id. at 5–6.
We agree with the Examiner that the compounds of Structure LRA-1
and the compounds of Structure 5-LI-1 do not form a proper Markush group.
“A Markush claim contains an ‘improper Markush grouping’ if: (1) The
species of the Markush group do not share a ‘single structural similarity,’ or
(2) the species do not share a common use.” 76 Fed. Reg. 7162, 7166 (2011)
(footnote omitted). “Members of a Markush group share a ‘single structural
similarity’ when they belong to the same recognized physical or chemical
class or to the same art-recognized class.” Id.
Here, the Examiner has found that compounds of Structure LRA-1 are
in the quinoline class, while compounds of Structure 5-LI-1 are in the
benzothiophene class, and that compounds according to the two structures
would be classified differently by the USPTO. The Structure LRA-1
compounds and the Structure 5-LI-1 compounds therefore are not in the
same recognized physical or chemical class or the same art-recognized class,
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and do not share a “single structural similarity.” Cf. In re Harnisch, 631 F.2d
716, 722 (CCPA 1980) (“Clearly, [the claimed compounds] are all coumarin
compounds which the board admitted to be ‘a single structural similarity.’”).
We thus agree with the Examiner that the inclusion of both compounds of
Structure LRA-1 and compounds of Structure 5-LI-1 in the Markush group
of claim 19 is improper.
Appellant argues that the Specification describes high penetration
prodrugs as comprising a “functional unit” (i.e., a moiety of a parent drug)
linked to a “transportational unit.” Appeal Br. 9. Appellant argues that “[t]he
specification further explains that ‘[a] transportational unit of an HPP
comprises a protonatable amine group that is capable of facilitating the
transportation or crossing of the HPP through one or more biological
barriers.’” Id. at 10. Appellant argues that “each species recited in claim 19
comprises a transportational group (i.e., a protonatable amine group)”
because both Structure LRA-1 and Structure 5-LI-1 comprise either
Structure W-1 or W-2 and “each of Structure W-1 and Structure W-2
comprises a protonatable amine group. . . . [E]ach Structure comprises a
basic nitrogen atom, and each Structure comprises a group ‘HA’ that, in
some embodiments, is an acid. Accordingly, each species recited in claim 19
possesses at least these structural similarities.” Id. at 10–11.
This argument is unpersuasive. As set out in the Federal Register
notice cited by the Examiner, “[m]embers of a Markush group share a
‘single structural similarity’ when they belong to the same recognized
physical or chemical class or to the same art-recognized class.” 76 Fed. Reg.
at 7166. Appellant has not disputed the Examiner’s finding that compounds
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of Structure LRA-1 are quinoline class compounds, while compounds of
Structure 5-LI-1 are benzothiophene class compounds. Nor has Appellant
pointed to evidence showing that compounds that comprise “a protonatable
amine group” or “a basic nitrogen atom” belong to the same recognized
physical or chemical class or to the same art-recognized class.
Appellant also argues that the rejection is inconsistent with In re
Harnisch, because, “[l]ike the claims in Harnisch, claim 19 recites
compounds belonging to a genus that is defined by the Appellant: namely,
one comprising species that each comprise a protonatable amine group.”
Appeal Br. 13.
This argument is also unpersuasive. The Harnisch court did not hold
that the Markush group at issue in that case “belong[ed] to a genus that is
defined by the Appellant,” as Appellant argues. Rather, the court concluded
that “all of appellant’s claimed compounds are dyes” and “they are all
coumarin compounds which the board admitted to be a ‘single structural
similarity.’” Harnisch, 631 F.2d at 722. Based on these factors, the court
stated:
We hold, therefore, that the claimed compounds all belong to a
subgenus, as defined by appellant, which is not repugnant to
scientific classification. Under these circumstances we consider
the claimed compounds to be part of a single invention so that
there is unity of invention. . . . The Markush groupings of
claims 1 and 3–8 are therefore proper.
Id. That is, because the compounds of the Markush group defined by the
appellants in Harnisch shared a common use and a single structural
similarity, the Markush grouping was proper.
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The Harnisch court did not hold that a proper Markush group can
comprise any genus that an applicant chooses to define. In fact, with regard
to Appellant’s argument that the compounds of claim 19 all comprise a
protonatable amine group, the Harnisch court expressly stated that “in
determining the propriety of a Markush grouping the compounds must be
considered as wholes and not broken down into elements or other
components.” Harnisch, 631 F.2d at 722 (discussing In re Jones, 162 F.2d
479 (CCPA 1947)).
Obviousness
Claims 19, 51, 54, 57, and 60 stand rejected as obvious based on
Trivedi, Järvinen, Mahfouz, and Walson. The Examiner finds that “Trivedi
teaches a composition comprising zileuton [and] water:ethanol (75:25).”
Ans. 7. Trivedi discloses the following structure for zileuton:

Trivedi 109, Fig. 1. The Examiner finds that “Trivedi does not teach the . . .
zileuton prodrug” of the elected species. Ans. 8. That is, the HO– group of
zileuton corresponds to the following structure in the elected species:

See Ans. 8, 27. In other words, the elected species is the N,N-diethyl glycine
ester of zileuton. See Ans. 10 (“[I]t would have been prima facie obvious . . .
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to modify zileuton moiety to comprise a N,N-diethylglycinyl promoiety at
the hydroxyl position.”).
The Examiner finds that “Jarvinen teaches prodrugs are commonly
derived from existing hydroxyl groups on the parent drug molecule, usually
by ester formation” and “N,N-diethyl glycinyl is an example of promoieties
for hydroxyl groups.” Ans. 8. The Examiner finds that Järvinen also teaches
that “amino acid derivatives such as N-propyl-, N,N-dimethyl, and diethyl
glycine esters, . . . were freely water-soluble and their half-lives for
bioconversion were less than 30 min[utes].” Id. at 9.
The Examiner finds that “Mahfouz teaches a series of amino acid
esters were synthesized as potential prodrugs of metronidazole” and teaches
that the “N,N-diethylglycinate hydrochloride derivative[] displayed higher
aqueous solubility, which exceeded that of the parent drug by a factor of
approximately 140.” Id. The Examiner finds that “Walson teaches
propacetamol is an acetaminophen prodrug . . . [and] is hydrolyzed to release
acetaminophen and pharmacologically inactive N,N-diethylglycine.” Id.
The Examiner concludes that it would have been obvious
to modify zileuton moiety to comprise a N,N-diethylglycinyl
promoiety at the hydroxyl position with an expectation of
success, since the prior art establishes that N,N-diethylglycinyl
is a promoiety for producing prodrugs commonly derived from
existing hydroxyl groups, is known to improve solubility of a
parent compound, and to hydrolyze to a parent compound and
an inactive N,N-diethylglycine.
Id. at 10.
We agree with the Examiner that the claimed composition, comprising
the elected species, would have been obvious to a person of ordinary skill in
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the art based on the cited references. Trivedi discloses that zileuton is a drug
used to treat asthma, and has the following structure:

Trivedi 109, right col. Trivedi also discloses that “[z]ileuton is [] poorly
soluble in water . . . , and the use of pharmaceutically acceptable organic co-
solvents might be necessary in liquid formulations that require
concentrations of drug above its aqueous solubility limit.” Id. at 110, left col.
Trivedi “examined the solubility and stability of zileuton in a ternary solvent
system consisting of water, ethanol (EtOH), and propylene glycol . . . with
the goal of arriving at a solvent composition which optimizes both solubility
and chemical stability.” Id.
Järvinen states that “[t]he prodrug approach is a valuable tool to
further optimize potent structures and to solve potential formulation or
delivery problems.” Järvinen 2. Järvinen teaches that “[p]rodrugs are
commonly derived from existing hydroxyl groups on the parent drug
molecule, usually by ester formation (Fig. 10).” Id. at 15.
Järvinen’s Figure 10 shows five “[e]xamples of promoieties for
hydroxyl groups,” including N,N-Diethyl glycinyl. Järvinen, Figure 10 and
figure legend. The Examiner finds, and Appellant does not dispute, that
modifying zileuton’s hydroxyl group (HO-) by forming the N,N-Diethyl
glycinyl ester results in the elected species of claim 19. See Ans. 10, Appeal
Br. 19 (disputing that it would have been obvious to make the ester
modification but not the identity of the resulting compound).
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Järvinen states that “[w]ater-soluble prodrugs are commonly obtained
as phosphates, succinates, or amino acid esters of the hydroxyl group.”
Järvinen 16 (emphasis added). “Amino acid esters, which are substrates for
endopeptidases in vivo, are also considered as suitable promoieties that
improve aqueous solubility.” Id. (endnote omitted). Järvinen states that
“[a]mino acid derivatives such as . . . diethtyl [sic] glycine esters, . . . were
freely water-soluble and their half-lives for bioconversion were less than 30
min.” Id. at 17. Järvinen therefore would have provided a skilled artisan with
a reasonable expectation that forming the diethyl glycine ester of a hydroxyl
group of a parent compound would result in a prodrug with increased water-
solubility.
Järvinen states that the chemical stability of amino acid derivatives
“was limited. In general, α-amino acid esters tend to be unstable in aqueous
solution due to an electron-withdrawing effect of the protonated amino
group.” Id. Järvinen states that, similarly, “succinate esters have a limited
chemical stability, due to intramolecular hydrolytic catalysis of the ester
bonds by the neighboring carboxyl group.” Id. at 16 (endnote omitted).
“These compounds are, therefore, marketed as a freeze-dried powder, which
is dissolved just prior to administration.” Id.
Mahfouz discloses synthesis and evaluation of “[a] series of amino
acid esters . . . as potential prodrugs of metronidazole with the aim of
improving aqueous solubility and therapeutic efficacy.” Mahfouz 841,
abstract. The “N,N-diethylglycinate hydrochloride . . . displayed higher
aqueous solubility, which exceeded that of the parent drug by [a] factor[] of
approximately 140.” Id. Mahfouz states that “[t]he prodrugs exhibited
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adequate chemical stability (half-life, t½, 4–15 h) in aqueous phosphate
solution of pH 7.4.” Id. “In conclusion, the designed amino acid esters . . .
might be considered as good candidates for water-soluble prodrug forms of
metronidazole.” Id.
Walson states that, “[u]ntil recently, . . . the only IV formulation of
acetaminophen was the acetaminophen prodrug propacetamol
hydrochloride.” Walson 763, left col. “This product must be dissolved in
saline or glucose just before infusion. Propacetamol is rapidly and
completely hydrolyzed in the blood into acetaminophen and
pharmacologically inactive N,N-diethylglycine by plasma esterases.” Id.
Based on these teachings, it would have been obvious to a person of
ordinary skill in the art to modify zileuton by forming the N,N-diethyl
glycine ester at the hydroxyl group, resulting in the elected species of
compound. The references provide adequate reason to combine their
teachings, because Trivedi teaches that zileuton is useful for treating asthma
but has poor aqueous solubility, and Järvinen teaches that water-soluble
prodrugs are commonly obtained as amino acid, including diethyl glycine,
esters of a parent drug. Järvinen also teaches that diethyl glycine derivatives
were found to be “freely water-soluble.” Järvinen 17. Mahfouz similarly
teaches that the diethyl glycine ester of metronidazole increased solubility
by a factor of 140. Mahfouz 841, abstract. The cited references thus would
have provided a reasonable expectation that the diethyl glycine ester of
zileuton would have increased water-solubility compared to the parent
compound.
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Appellant argues, however, that “Jarvinen cautions its reader against
risks of decreased chemical stability resulting from prodrug formation,
including the structural modification proposed by the Office.” Appeal Br.
19. That is,
[t]he person having ordinary skill in the art would understand
that N,N-diethyl glycine ester is an example of an α-amino acid
ester. Thus, Jarvinen plainly identifies the diethyl glycinyl ester
promoiety as one that suffers from reduced chemical stability.
Further still, Jarvinen also highlights the instability of α-amino
acid esters (such as N,N-diethyl glycine ester) in aqueous
solution.
Id.
Consistent with Appellant’s argument, Järvinen states that the
chemical stability of amino acid derivatives “was limited” and that α-amino
acid esters generally “tend to be unstable in aqueous solution.” Järvinen 17.
However, Järvinen notes that succinate esters also tend to have limited
stability, which simply requires that they be marketed as a freeze-dried
powder that is dissolved just prior to administration. Id. at 16.
Thus, a skilled artisan would have viewed the limited chemical
stability disclosed by Järvinen as likely to require formulating the elected
species of compound as a dry powder, but would not have expected the
limited stability to make the compound unusable therapeutically. Walson, in
fact, discloses that propacetamol is an acetaminophen prodrug used
clinically and formulated in just this way.
We therefore do not agree with Appellant that Järvinen’s discussion of
the chemical stability, in aqueous media, of amino acid ester prodrugs would
have dissuaded a skilled artisan from making the combination proposed by
the Examiner.
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Appellant also argues that there would not have been a reason to
combine the teachings of Trivedi and Järvinen because Järvinen pertains
almost exclusively to prodrug design and synthesis, while Trivedi is
“concerned with the formulation of an active agent (e.g., in a specific solvent
composition).” Appeal Br. 16–17. “Trivedi and Jarvinen contemplate
entirely different approaches to overcoming poor drug properties and
explore them in different contexts. . . . The references thus direct their
readers to different methods of improving drug properties, and neither
reference teaches or suggests the approach adopted by the other.” Id. at 17.
This argument is also unpersuasive. Järvinen states that “[t]here are
various approaches that can be applied to overcome poor properties of drug
formulation and delivery. Some of these problems can be overcome by
dosage form design. . . . An important strategy approach to improve poor
drug formulation and delivery properties is prodrug technology.” Järvinen 2.
Thus, Järvinen provides evidence that Trivedi’s approach of changing the
solvent composition, and Järvinen’s approach of making prodrug forms of
an active agent were both known methods of addressing poor properties of a
drug, such as low solubility in aqueous media. A skilled artisan therefore
would have recognized Järvinen’s prodrug approach as being among the
obvious methods of addressing the poor water-solubility of zileuton.
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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
19 Improper Markush
Group
19
19, 51, 54,
57, 60
103(a) Trivedi, Järvinen,
Mahfouz, Walson
19, 51, 54,
57, 60

Overall
Outcome
19, 51, 54,
57, 60

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED