RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY et al.

Patent Trials and Appeals Board

Mar 2, 2021

2020004190 (P.T.A.B. Mar. 2, 2021)

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.
16/053,537 08/02/2018 Edmond J. LaVoie 00535.013US6 3997
53137 7590 03/02/2021
VIKSNINS HARRIS PADYS MALEN LLP
7851 Metro Parkway
Suite 325
Bloomington, MN 55425
EXAMINER
O DELL, DAVID K
ART UNIT PAPER NUMBER
1625
NOTIFICATION DATE DELIVERY MODE
03/02/2021 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):
docketing@vhpmlaw.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte EDMOND J. LAVOIE, AJIT PARHI, DANIEL S. PILCH,
YONGZHENG ZHANG, and MALVIKA KAUL

Appeal 2020-004190
Application 16/053,537
Technology Center 1600
Before ERIC B. GRIMES, FRANCISCO C. PRATS, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.

NEWMAN, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claim 1. We have jurisdiction under
35 U.S.C. § 6(b). We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. Appellant identifies the real party in interest as “Rutgers,
The State University of New Jersey.” Appeal Br. 2. Herein, we refer to the
Appeal Brief filed February 2, 2020 (“Appeal Br.”), the Examiner’s Answer
filed March 18, 2020, (“Ans.”), and the Reply Brief filed May 15, 2020
(“Reply Br.”).
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STATEMENT OF THE CASE
The emergence of Multidrug Resistant (MDR) bacterial pathogens
(e.g. methicillin-resistant Staphylococcus aureus (MRSA),
Acinetobacter baumannii-calcoaceticus complex (ABC), etc.) has
increased concerns as to the adequacy of current antimicrobials and
pathogen treatment methods. The lethality of such pathogens,
particularly MRSA, has often led to treatment methods that are
experimental or would otherwise normally be avoided in standard
clinical practice. . . . The growing threat from MDR pathogens
highlights a critical need for additional antimicrobials. In this
connection, there is a pressing need for new antibiotics that exhibit
novel mechanisms of action or that are able to circumvent known
resistance pathways.
Spec. 1:12–22.
The Specification discloses “antibiotic compounds that are highly
solu[ble] and that can be formulated for administration as antibiotic agents.”
Id. at 2:9–10.
CLAIMED SUBJECT MATTER
Claim 1, directed to a chemical compound, is on appeal2 and is
reproduced below:
1. The compound:

Appeal Br. 13 (Claims App.).

2 Appellant addresses the status of claims 2 and 3 at Appeal Br. 4. As those
claims are not before us on appeal, we take no position on the status or
patentability of either claim.
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REFERENCES
The prior art relied upon by the Examiner is:
Name Reference Date
David Brown et al.
“Brown”
WO 2007/107758 A1 Sept. 27, 2007
David J. Haydon et al.
“Haydon”3
53: J. Med. Chem., 3927–
36 (2010)
April 28, 2010

REJECTION
Claim 1 is rejected under pre-AIA 35 U.S.C. § 103(a) as being
obvious over Brown and Haydon. Answer 3–4.

OPINION
A. Issues
The Examiner has rejected claim 1 as obvious based on Brown and
Haydon. Id. The Examiner finds that Brown and Haydon teach three prior
art compounds, described and reproduced in the chart below, with the
compound of claim 1 provided for comparison:

3 Creating an Antibacterial with in Vivo Efficacy: Synthesis and
Characterization of Potent Inhibitors of the Bacterial Cell Division Protein
FtsZ with Improved Pharmaceutical Properties, 53: J. MED. CHEM., 3927–
36 (2010).
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Compound as
identified in Brown
Compound as
identified in Haydon
Structure
139 2
217 8e
218 8j

Compound of claim 1

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Compound 139 of Brown (“Brown 139/Haydon 2”) differs from the
claimed compound in that it has a 6 position chlorine where the claimed
compound has a trifluoride (CF3). Ans. 4. Compound 217 (“Brown
217/Haydon 8e”) has a benzothiazole group instead of a thiazolo[5,4-
b]pyridine ring. Id. at 4–5. Compound 218 (“Brown 218/Haydon 8j”) also
has a benzothiazole group instead of a thiazolo[5,4-b]pyridine ring as well as
a 6 position chlorine where the claimed compound has a trifluoride (CF3).
Id. at 5.
Issue
The Examiner finds that Brown identified compounds 139, 217, and
218 as “in the A group of most potent compounds” based on their
antibacterial activity in a liquid media test. Id. at 5; Brown at 161–2.
The Examiner finds that Haydon explored the structure-activity
relationship (SAR) of compounds Brown 139/Haydon 2 and Brown
218/Haydon 8j in a murine model of staphylococcal infection. Ans. 5. The
Examiner finds that Haydon disclosed that compound Brown 139/Haydon 2
was effective against infection in multiple administration methods while
Brown 218/Haydon 8j was effective in only the highest potency
administration (intraperitoneal). Ans. 5–6. The Examiner finds Haydon
discloses that 5-substituted-1,3-benzothiazol-2-ylmethoxy compounds such
as Brown 218/Haydon 8j bound to plasma too tightly to be further
considered for drug development purposes (meaning the drug was not
pharmacologically active, as it was bound to plasma proteins). Id. The
Examiner finds that Haydon disclosed:
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Replacing the benzothiazole substituent with a thiazolopyridine
[as in Brown 139/Haydon 2] reduced the antibacterial activity
but also reduced the plasma protein binding. Furthermore, the
metabolic stability of the thiazolopyridine was improved
compared to the henzothiazole, resulting in an approximately
15-fold reduction in clearance following intravenous
administration in the mouse.
Ans. 7 (quoting Haydon 3932–3). The Examiner finds that the improved
overall performance of compound Brown 139/Haydon 2, which Haydon
attributed to the thiazolopyridine substitution, would have motivated the
skilled artisan interested in developing antibacterial compounds to modify
compounds having a benzothiazole group to substitute benzothiazole group
with thiazolopyridine. Id. at 6–7. Specifically, the Examiner finds the
artisan would have been motivated to modify compound Brown 217/Haydon
8e “by replacing the benzothiazole with thiazolopyridine” to reduce the
plasma protein binding and reduce drug clearance, which both equate to
higher drug efficacy. Id. at 7. The Examiner finds that, alternatively, the
skilled artisan would have been motivated “to replace the Cl with a -CF3 to
arrive at the compound of claim 1 since similar potency would be expected
based upon the data for 8e and 8j.” Id.
Appellant argues the Examiner’s combination of prior art fails to
render the claims obvious because “the Office has failed to provide adequate
evidence that one skilled in the art would have selected Compound 8e as a
lead compound.” Appeal Br. 9. Appellant submits that the Office has not
sufficiently explained why the skilled artisan would have selected the
identified compounds over “other more potent compounds identified in the
table,” particularly when “it would have been clear to one skilled in the art
that the data pointed to [Brown 139/Haydon 2] as the lead compound.” Id.
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Appellant also argues that, to the extent the Examiner has shown a prima
facie case of obviousness, the compound of claim 1 “has an unexpected and
improved in vivo half-life that renders it unobvious” over the Brown/Haydon
compounds. Appeal Br. 5. Appellant also argues that the claimed
compound is not obvious “because it is useful to prepare the compound
recited in issued claim 11 of parent patent United States Patent Number
9,458,150.” Id. In support of the arguments, Appellant cites the Declaration
of inventor Professor Edmond J. LaVoie under 37 C.F.R. § 1.132, dated
April 30, 2019 (“LaVoie Dec.”). We discuss Appellant’s evidence further
below.
The issue on appeal is whether the preponderance of the evidence of
record supports the Examiner’s conclusion of obviousness.
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Prima facie obviousness may be rebutted with evidence of secondary
considerations and when such evidence is submitted, all of the evidence is
considered anew. In re Piasecki, 745 F.2d 1468, 1472–73 (Fed. Cir. 1984).
Secondary considerations include, inter alia, long-felt but unsolved needs,
failure of others, and unexpected results. In re Rouffet, 149 F.3d 1350, 1355
(Fed. Cir. 1998).
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Analysis
Looking to the Examiner’s findings and reasoning concerning the
combination of Brown and Haydon, we agree that the compound of claim 1
would have been prima facie obvious. Each of compounds Brown
139/Haydon 2, Brown 218/Haydon 8j, and Brown 217/Haydon 8e were
potent antibacterial compounds in multiple tests, making them suitable
subjects for further drug development. Brown 162. Haydon confirmed that
each of these compounds was effective in a murine model of staphylococcal
infection, and further analyzed benefits in antibacterial effect conferred by
specific chemical structures within the compounds. Haydon 3931–3.
Haydon demonstrated the benefit of modifying Brown 218/Haydon 8j,
which provides similar motivation to modify Brown 217/Haydon 8e based
on its advantageous chemical structure. However, considering the totality of
the evidence of record, we reach a different conclusion.
The LaVoie Declaration was submitted in response to the Examiner’s
statement in the non-final Office Action dated December 28, 2018, that the
skilled artisan would have been “motivated to replace the Cl [of compound
Brown 139/Haydon 2] with a -CF3 to arrive at the compound of claim 1
since similar potency would be expected.” LaVoie Dec. ¶ 3 (citing Office
action at 8).
Dr. LaVoie explains that the compound of claim 1, referred to in the
Declaration as TXA-7-07, is a “synthetic intermediate that can be
used to prepare the compound TXA-7-09.” LaVoie Dec. ¶ 5. Compound
TXA-7-09 is reproduced below along with the corresponding 6-chloro
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compound TXY-5-41, which is identical except that the –CF3 of TXA-7-09
is replaced with a –C1. Id. ¶ 5.

Dr. LaVoie declares that “[f]ollowing administration, TXA-7-09 and
TXY-5-41 are hydrolyzed to the corresponding amides TXA-7-07 and
PC190723,” shown below. Id. TXA-7-07 is the compound of claim 1.

Dr. LaVoie declares that “the half-life of the hydrolysis product TXA-
7-07 was found to be 6.5 fold greater than the half-life of PC190723 after
intravenous administration in mice when measured as described by Malvika
Kaul, et al., Antimicrob. Agents Chemother., 2015, 59, 4845–4855”
(“Kaul”). Id. Dr. LaVoie additionally declares that Kaul reported that
“TXA-7-09 was found to be more potent than TXY-5-41 following
intravenous administration in a murine septicemia model against
Staphylococcus aureus infection (MSSA strain ATCC 19636).” Id. ¶ 6.
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Dr. LaVoie further declares that the bioavailability of the hydrolysis
product TXA-7-07 (the compound of claim 1), is 95% compared to 29.6% of
PC190723, the hydrolysis product of TXY-5-41. Id. ¶ 7.
Finally, Dr. LaVoie declares that Kaul reported that “oral
administration of 48 mg/kg of TXA-7-09 in the septicemia model described
by [Kaul resulted in] a 100% cure from a methicillin-resistant S. aureus
infection” while four times the dose of TXY-5-41 was required to obtain a
similar response. Id. ¶ 8. “When TXY-5-41 was administered at 64 mg/kg
there were 0% survivors.” Id.
The Examiner responds that the “unexpected results argument is
based on a comparison of non-prior art prodrug compounds” and that the
comparison is not to a compound that is closer to the claimed compound.
Ans. 7. We do not agree, as the declaration makes clear that metabolite
PC190723 corresponds to compound Brown 139/Haydon 2, which is one of
the compounds identified in the prior art and the compound upon which the
claim was rejected. LaVoie Dec. ¶ 3 (citing Office action at 8).
The Examiner further argues that “[t]here is no biological data for the
compound of claim 1 in the specification or declaration.” Id. While the
administered compounds compared are prodrugs, the record provides
sufficient evidence to establish that the effects measured for each
administered compound are caused by the metabolite, and that it is the
metabolite that is biologically effective in each case. LaVoie Dec. ¶¶ 5–8.
Moreover, TXA-7-07 provides unexpectedly superior results in that it has a
significantly longer half-life, resulting from a lower clearance rate from the
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subject as well as a more effective antibacterial effect at lower doses than a
similar compound. Id.
Appellant’s data concerning the effectiveness of TXA-7-07 in vivo
provides persuasive objective evidence of nonobviousness. The Examiner’s
response relies heavily on the prima facie case, and the reasoning from
Haydon suggesting that modification of compounds having benzothiazole by
replacing the benzothiazole with thiazolopyridine would result in improved
antibacterial function. Ans. 6−7. The Examiner has not, however, provided
persuasive evidence or scientific reasoning explaining why the results
Appellant has produced would have been expected.
When the Examiner’s prima facie case is considered anew, in light of
all the evidence of record, we are unpersuaded that claim 1 would have been
obvious over Brown and Haydon. Appellant has provided persuasive
argument and objective evidence of nonobviousness that outweighs the
evidence of obviousness. Mintz v. Dietz & Watson, Inc., 679 F.3d 1372,
1379 (Fed. Cir. 2012) (“Obviousness requires . . . walk[ing] a tightrope
blindfolded (to avoid hindsight)—an enterprise best pursued with the safety
net of objective evidence.”) This is not a case where the prima facie case is
so strong that it controls the obviousness determination. See Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007). We thus reverse the
rejection of claim 1.

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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1 103 Brown, Haydon 1

REVERSED