VLP Therapeutics, LLC

Patent Trials and Appeals Board

Oct 29, 2021

2021001036 (P.T.A.B. Oct. 29, 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.
14/962,805 12/08/2015 Ryuji UENO Q223961 4244
23373 7590 10/29/2021
SUGHRUE MION, PLLC
2000 PENNSYLVANIA AVENUE, N.W.
SUITE 9000
WASHINGTON, DC 20006
EXAMINER
PARKIN, JEFFREY S
ART UNIT PAPER NUMBER
1648
NOTIFICATION DATE DELIVERY MODE
10/29/2021 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):
PPROCESSING@SUGHRUE.COM
USPTO@sughrue.com
sughrue@sughrue.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte RYUJI UENO and WATARU AKAHATA1
Appeal 2021-001036
Application 14/962,805
Technology Center 1600
Before ERIC B. GRIMES, TAWEN CHANG, and JAMIE T. WISZ,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to virus-
like particles displaying an antigen, which have been rejected for lack of
enablement. We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 Appellant identifies the real party in interest as VLP Therapeutics, Inc.
Appeal Br. 2; Request to Correct or Update the Name of the Applicant, filed
June 10, 2021. “Appellant” refers to “applicant” as defined in 37 C.F.R.
§ 1.42.
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Application 14/962,805

2
STATEMENT OF THE CASE
“Virus-like particles (VLPs) are multiprotein structures that mimic the
organization and conformation of authentic native viruses but lack the viral
genome, potentially yielding safer and cheaper vaccine candidates.” Spec.
1:19–22. “Chikungunya virus (CHIKV) has infected millions of people in
Africa, Europe and Asia since . . . 2004.” Id. at 2:19–21.
“In one embodiment, the present invention provides a Chikungunya
virus like particle or a Venezuelan equine encephalitis virus like particle
comprising a Chikungunya or Venezuelan equine encephalitis virus
structural polypeptide and at least one antigen.” Id. at 21:21 to 22:1.
Claims 1, 3–5, 7–10, 14, 15, and 21 are on appeal. Claim 1, the only
independent claim, is illustrative and is reproduced below:
1. A Chikungunya virus (CHIKV) or Venezuelan equine
encephalitis virus (VEEV) virus-like particle which is capable
of being self-assembled,
wherein said virus-like particle comprises capsid and
envelope proteins,
wherein said virus-like particle comprises a Chikungunya
virus (CHIKV) or Venezuelan equine encephalitis virus
(VEEV) envelope protein with at least one antigen inserted
therein,
and wherein the spatial distance between the N-terminal
residue and the C-terminal residue of the antigen is 30Å or less.

OPINION
Claims 1, 3–5, 7–10, 14, 15, and 21 stand rejected under 35 U.S.C.
§ 112, first paragraph, for lack of enablement. Ans. 3.2 The Examiner finds

2 The Examiner withdrew the rejection based on indefiniteness. Ans. 8–9.
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Application 14/962,805

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that “[t]he claim breadth is considerable and encompasses an inordinate
number of putative insertion sites and variant fusion proteins. The envelope
coding portion encompasses four proteins: E3, E2, 6k, and E1.” Id. at 4. The
Examiner finds that “any given heterologous antigen could be inserted
anywhere within these proteins,” but “the disclosure only discusses a limited
number of potential insertion sites.” Id. at 5.
The Examiner also finds that “[t]he disclosure fails to provide
adequate guidance pertaining to the CHIKV or VEEV envelope structure
vis-à-vis the identification of suitable insertion sites.” Id. The Examiner asks
“What is the maximum length that can be inserted without disrupting protein
function?” and “which regions of these envelope proteins can tolerate
insertions without diminishing wildtype Env activity?” Id. at 5, 6.
The Examiner finds that “[t]he disclosure provides a limited number
of working embodiments . . . all within the E2 protein. The specification did
not identify any additional suitable insertion sites within E2 or any of the
other CHIKV or VEEV proteins.” Id. at 7. Specifically, “[s]hort
heterologous antigens were inserted into regions 519/520 and 532/533 of
CHIKV and VEEV. No other chimeric envelopes were generated.” Id.
The Examiner also finds that “[t]here is considerable unpredictability
in the prior art.” Id. 3 The Examiner points to evidence that “demonstrated
that single amino acid substitutions are sufficient to alter or inhibit Env

3 The Examiner cites “Akahata and Nabel, 2012; Kuo et al., 2012; Urakami
et al., 2017” (Ans. 7) as supporting evidence, but does not provide full
citations for these references. We understand Akahata and Kuo to be the
references cited on the Form PTO-892 mailed Nov. 29, 2018, and previously
made of record in the parent application. We understand Urakami to be the
reference that was made of record in the instant application on Jan. 9, 2020.
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Application 14/962,805

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activity.” Id. (citing Akahata4 and Kuo5). The Examiner finds that Urakami6
“examined putative antigen insertion sites in CHIKV based upon the
envelope crystal structure and reported that antigens needed to be located in
the surface loop of the CHIKV Env to obtain proper folding and
expression.” Id. at 8.
The Examiner concludes that “when all the aforementioned factors are
considered in toto, the skilled artisan would reasonably conclude that the
claim breadth is not commensurate in scope with the support in the
disclosure.” Id.
Appellant argues that “that persons of skill in the art could readily
insert . . . an antigen at different positions within a CHIKV or VEEV
envelope protein, and screen for virus-like particles containing the inserted
antigen.” Appeal Br. 9. Appellant argues that “exemplary envelope protein
sequences of CHIKV and VEEV were already known to those of skill in the
art . . . as were the genetic engineering techniques for inserting a particular
peptide sequence into a precise desired location in a target polypeptide.” Id.
at 10. Appellant argues that “such techniques were routine in the art, and
would not require undue experimentation.” Id.
Appellant also argues that, “as described and exemplified in, e.g.,
Examples 1, 2, 4 and 7 of the present specification . . . , virus-like particle

4 Akahata et al., “A Specific Domain of the Chikungunya Virus E2 Protein
Regulates Particle Formation in Human Cells: Implications for Alphavirus
Vaccine Design,” Journal of Virology 86:8879–8883 (Aug. 2012).
5 Kuo et al., “Cell-based analysis of Chikungunya virus E1 protein in
membrane fusion,” Journal of Biomedical Science 19:44 (Apr. 2012).
6 Urakami et al., “Development of a Novel Virus-Like Particle Vaccine
Platform That Mimics the Immature Form of Alphavirus,” Clinical and
Vaccine Immunology 24(7):1–14 (2017).
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formation can readily be determined by expression of a virus structural
polypeptide in cells in vitro, followed by density gradient centrifugation and
a routine immunoassay test (such as Western blot).” Id. Appellant argues
that “such screening techniques (centrifugation followed by immunoassay
against a known antigen) were routine in the art, and would not require
undue experimentation.” Id.
We agree with Appellant that the Examiner has not shown, by a
preponderance of the evidence, that undue experimentation would have been
required to practice the full scope of the claims on appeal. See In re Wright,
999 F.2d 1557, 1561–62 (Fed. Cir. 1993):
When rejecting a claim under the enablement requirement of
section 112, the PTO bears an initial burden of setting forth a
reasonable explanation as to why it believes that the scope of
protection provided by that claim is not adequately enabled by
the description of the invention provided in the specification of
the application.
The Examiner has rejected the claims on the basis that they do not
specify particular insertion sites for an antigen in an envelope (Env) protein
from Chikungunya virus or Venezuelan equine encephalitis virus, and the
“skilled artisan would be required to test an inordinate number of Env
variants to ascertain the optimal location sites.” Ans. 10.7
Appellant’s Specification states that “[i]n one embodiment, the
antigen can be fused with any site of the Chikungunya or Venezuelan equine
encephalitis virus structural polypeptide.” Spec. 31:2–4 (emphasis added).
“For example, the antigen may be directly or indirectly linked to N- or C-

7 Enablement, of course, does not require that a claimed invention be
“optimal,” only that it be disclosed in enough detail that a person of ordinary
skill in the art can make and use it without undue experimentation.
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termin[us] . . . , or the antigen may be inserted into Chikungunya or
Venezuelan equine encephalitis virus structural protein (e.g. capsid, E3, E2,
6K, or E1).” Id. at 31:4–10.
In the absence of persuasive evidence to the contrary, these statements
in the Specification must be taken as accurate. See In re Wright, 999 F.2d
1562 (“[T]he PTO bears an initial burden [of proof] . . . ; this includes, of
course, providing sufficient reasons for doubting any assertions in the
specification as to the scope of enablement.”). See also In re Marzocchi, 439
F.2d 220, 223 (CCPA 1971):
[A] specification disclosure which contains a teaching of the
manner and process of making and using the invention in terms
which correspond in scope to those used in describing and
defining the subject matter sought to be patented must be taken
as in compliance with the enabling requirement of the first
paragraph of § 112 unless there is reason to doubt the objective
truth of the statements contained therein which must be relied
on for enabling support.
The Examiner points to Akahata, Kuo, and Urakami as evidence that
“[a]round the time of filing it was well-known that VLPs display widely
varying properties that cannot be determined a priori.” Ans. 9. As the
Examiner noted, however, “[t]he effective filing date of the instant
application is 16 February, 2012.” Id. at 7.
Akahata was published in August 2012. Akahata 8879. Kuo was
published April 21, 2012. Kuo 11. Urakami was published in 2017.
Urakami 1. Thus, the cited references were all published after the effective
filing date of Appellant’s application. “Enablement . . . is determined as of
the application filing date.” In re Brana, 51 F.3d 1560, 1567 n.19 (Fed. Cir.
1995). The Examiner has not pointed to evidence in the record showing that,
as of Appellant’s effective filing date, those skilled in the art recognized that
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“VLPs display widely varying properties that cannot be determined a priori.”
Ans. 9.
In addition, even if the cited references are considered to be “evidence
of the state of art existing on the filing date of an application,” In re Hogan,
559 F.2d 595, 605 (CCPA 1977), they do not persuasively show that undue
experimentation would be required to practice the claimed invention.
Akahata states that “CHIKV 37997 strain VLPs . . . could be
produced efficiently but th[e] yields of CHIKV OPY-1 strain . . . were low.”
Akahata 8879, left col. “To identify the viral gene responsible for increased
VLP generation, [Akahata] prepared chimeric VLP expression vectors” that
replaced part of the OPY-1 genome with that of the 37997 genome. Id.
Akahata reports that the E2 gene, and specifically “the NH2-terminal region
(aa 1 to 290) was necessary and sufficient for efficient VLP synthesis.” Id. at
8879, right col.
Akahata states that “[t]he sequences of 37997 and OPY-1 differ in this
region by 12 amino acids,” so “site-specific mutations were introduced
individually at these sites.” Id. Akahata found that “[e]leven of the 12
mutants synthesized VLPs at levels similar to those of” the chimera with the
NH2-terminal region from 37997, while “the N234K mutation from OPY-1
produced a >3-fold reduction in VLP release.” Id.
Thus, Akahata’s data show that the vast majority (11 out of 12) of the
mutations in E2 had little effect on VLP synthesis, while one mutation
decreased VLP release greater than 3-fold. Even considering the N234K
mutation, however, the Examiner has not shown that a 3-fold reduction in
VLP synthesis would be too low to allow a skilled artisan to use the claimed
invention.
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Kuo states that “[v]iral membrane fusion with a cell membrane is
mediated by the E1 glycoprotein” of Chikungunya virus. Kuo 2, left col. “To
explore the structure and fusogenicity of the E1 protein, four E1 residues
(G91, V178, A226, and H230) were selected for change by mutation.” Id. at
2, right col. Kuo reports that “cells infected by CHIKV E1-H230A mutant
. . . showed little fusion activity, and those bearing CHIKV E1-G91D mutant
completely lost the ability to induce cell-cell fusion.” Id. at 1, abstract.
However, the “CHIKV E1-A226V and E1-V178A mutants exhibited the
same membrane fusion capability as wild type,” although their cholesterol
dependence and pH threshold for fusion were different. Id.
Thus, while Kuo provides evidence that certain substitution mutations
in the Chikungunya virus E1 protein can affect the ability of that protein to
induce membrane fusion, it does not provide any evidence regarding the
potential effect of inserting an amino acid sequence (i.e., an antigen) into E1
or any other envelope protein, nor does it provide evidence regarding VLP
synthesis or antigenicity of the resulting fusion protein.
The Examiner cites Urakami as evidence that “that antigens needed to
be located in the surface loop of the CHIKV Env to obtain proper folding
and expression.” Ans. 8. However, Akahata states that “[t]he CHIKV E1/E2
(OPY-1 strain) was modeled based on Protein Data Bank (PDB) code 3N43
and displayed using PyMOL.” Akahata 8881, legend to Fig. 2. Appellant’s
Specification discloses exemplary CHIKV and VEEV structural polypeptide
sequences (Spec. 24–30; SEQ ID NO: 1–3) and states that “the antigen used
for the particle provided by the present invention can be designed using a
free software including PyMOL” (id. at 21:7–10).
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Application 14/962,805

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In view of the Specification’s disclosure, the Examiner has not
persuasively explained why undue experimentation would have been
required to determine an antigen insertion location that would place the
antigen in a surface loop of an envelope protein.
In summary, we conclude that the rejection of the claims for lack of
enablement is not supported by a preponderance of the evidence. We
therefore reverse the rejection of claims 1, 3–5, 7–10, 14, 15, and 21 under
35 U.S.C. § 112, first paragraph.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 3–5, 7–
10, 14, 15,
21
112, first
paragraph
Nonenablement 1, 3–5, 7–
10, 14, 15,
21

REVERSED