LIFE SCIENCE INKUBATOR BETRIEBS GMBH & CO. KG

Patent Trials and Appeals Board

Sep 1, 2021

2020005892 (P.T.A.B. Sep. 1, 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.
16/354,739 03/15/2019 Victoria Demina Q245970 4205
23373 7590 09/01/2021
SUGHRUE MION, PLLC
2000 PENNSYLVANIA AVENUE, N.W.
SUITE 9000
WASHINGTON, DC 20006
EXAMINER
ZOU, NIANXIANG
ART UNIT PAPER NUMBER
1648
NOTIFICATION DATE DELIVERY MODE
09/01/2021 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 VICTORIA DEMINA, HEIKO MANNINGA,
ARMIN GÖTZKE, and ALEXANDER GLASSMANN
Appeal 2020-005892
Application 16/354,739
Technology Center 1600
Before ULRIKE W. JENKS, JENNIFER MEYER CHAGNON, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims to a method of treating a central
nervous system disease or a neurological, neuronal, or neurodegenerative
disorder by administering virus-like particles (VLP) loaded with a drug to a
subject in need. 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(a). Appellant identifies the real party in interest as Life Science
Inkubator Betriebs GmbH & Co. KG. (Appeal Br. 3.)
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Application 16/354,739

2
STATEMENT OF THE CASE
Appellant’s Specification states that “[o]ne of the major challenges in
modern medicine is the drug delivery.” (Spec. 1.) “Drug delivery into the
central nervous system (CNS), in particular into the brain, is a great
challenge, since the active ingredients at first have to cross the blood-brain
barrier[, BBB,] and then have to reach the target cells.” (Id. at 2.)
Appellant’s invention is directed at a drug delivery system “that allows drug
transport into CNS cells, i.e. a drug delivery over the BBB.” (Id. at 3.)
Claims 1–12 are on appeal. Claim 1, reproduced below, is illustrative
of the claimed subject matter:
1. A method of treating a central nervous system (CNS) disease
or a neurological, neuronal or neurodegenerative disorder, the
method comprising:
intravenously administering a drug delivery system
composed of virus-like particles (VLP) loaded with a drug into a
subject in need thereof, wherein said subject has a
physiologically intact blood-brain barrier (BBB),
wherein the VLP cross the blood-brain barrier (BBB) of
the subject together with the drug,
wherein the VLP are composed of VPl comprising an
amino acid sequence which is at least 80 % identical to the amino
acid sequence according to SEQ ID NO: 1 over its entire length,
and
wherein in said method, said drug delivery system does
not further contain, and said subject is not administered, an
additive that decreases the integrity of, or increases the
permeability of, the BBB.
(Appeal Br. 21.)

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Application 16/354,739

3
The prior art relied upon by the Examiner is:
Name Reference Date
GenBank Accession No:
AAC59325.1
1998
Claudia Goldmann et
al.
Molecular Cloning and
Expression of Major
Structural Protein
VP1 of the Human
Polyomavirus JC
Virus: Formation of
Virus-Like Particles
Useful for
Immunological and
Therapeutic Studies,
73(5) J. Virol., 4465–
69
1999
J.B. Schulz Anti-apoptotic gene
therapy in Parkinson’s
disease, 70 J. Neural
Transm. (Suppl.) 467–
76
2006
Jean Pierre Louboutin
et al.
Efficient CNS gene
delivery by intravenous
injection, 7(11) Nature
Methods, 905–907
2010

The following ground of rejection by the Examiner is before us on
review:
Claims 1–12 under 35 U.S.C. § 103(a) as unpatentable over
Goldmann, Louboutin, Schulz, and GenBank Accession AAC59325.1.
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Application 16/354,739

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DISCUSSION
The Examiner found that “Goldmann is a research article on JCV2
VLPS3 for immunological and therapeutic studies.” (Ans. 9.) The Examiner
found that Goldmann teaches VLPs are “useful for PML4 vaccine
development and represent a potential new transporter system for human
gene therapy.” (Final Action 4 (citing Goldman Abstr.).)
The Examiner found that Goldmann teaches recombinant VP15 from
JCV forms VLP and that exogenous DNA could be efficiently packaged into
those VP1 VLP. (Final Action 4.) The Examiner further found that
Goldmann teaches that the VLPs “showed efficient binding to B and T cells,
as well as to kidney cells” and were “internalized and transported to the
nucleus.” (Id.) In addition, the Examiner found that Goldmann teaches
intravenous administration of the VLP and that no immune response
occurred from that administration. (Id.) The Examiner further found that
Goldmann teaches the packaged DNA was successfully transferred into
COS-7 cells. (Id.)
The Examiner found that Goldmann also teaches that the kidneys
represent a major site of JCV persistence and B cells may function as a ferry
for JCV to enter the brain. (Id. (citing Goldmann 4468).) The Examiner
concluded that “[t]his teaching suggest[s] that VP1 VLPs may be used as a
vector [] for delivery of therapeutic substances to specific sites such as
kidney and brain (i.e. passing the BBB).” (Id.)

2 JCV is the human polyomavirus JC virus. (Goldmann 4465.)
3 VLP are virus-like particles.
4 PML is progressive multifocal leukoencephalopathy, which is a viral
demyelinating disease in humans. (Goldmann 4465.)
5 VP1 is a major structural protein of JCV. (Goldmann 4465.)
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Application 16/354,739

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The Examiner found that “GenBank:AAC59325.1 discloses the amino
acid sequence of JCV VP1 that is at least 99% identical to SEQ ID NO:1 as
claimed.” (Final Action 6.) The Examiner found that although Goldmann
does not teaches the details of the amino acid sequence of the VP1, “one of
ordinary skill in the art would have reasonabl[y] expected” it would have
been at least 80% identical to the claimed SEQ ID NO:1. (Id.)
Alternatively, the Examiner found that it would have been obvious for one
of ordinary skill in the art to have used the VP1 disclosed in GenBank
AAC59325.1 “because of it[s] ready availability.” (Id.)
The Examiner found that Louboutin teaches recombinant SV40-
derived viral vectors administered intravenously can deliver transgenes to
the central nervous system. (Final Action 5.) The Examiner found that
Louboutin teaches a replication defective SV40 vector was produced from a
transfected COS-7 cell line. (Id.) The Examiner found that SV40 has VP1
proteins that are as high as 75% identical to SEQ ID NO:1. (Final Action
12.) The Examiner explained that the “[t]eachings of Louboutin indicate
that VLPs of a poliovirus (SV40) have been used as a carrier in delivering
nucleic acid agents across BBB successfully without knowing a clear and
unquestionable BBB-crossing mechanism.” (Id. at 13.)
The Examiner found that neither Goldamnn nor Louboutin explicitly
teaches treating a neurological disorder using the virus-like particle loaded
with a drug.
The Examiner found that Schulz teaches that apoptosis has been
implicated in Parkinson’s disease (Final Action 5.) The Examiner also
found that Schulz teaches “that use of viral vectors to either express anti-
apoptotic proteins or to downregulate pro-apoptotic proteins has the major
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advantage of addressing selective molecular targets, bypassing the blood-
brain-barrier to specifically target the nigostriatal pathway by their
stereotaxic application and by the choice of the appropriate virus and
promot[e]r. See e.g. Abstract.” (Id. at 5–6.)
The Examiner concluded that one of ordinary skill in the art would
have found it obvious to develop a gene therapy treatment approach for
Parkinson’s disease patients by delivering the genes expressing proteins of
interest disclosed in Schulz with the virus particles disclosed in Goldmann or
Louboutin, “[g]iven the state of the art that viral vectors are used in
delivering transgenes in the development of gene treatment for CNS
disease.” (Final Action 6.) The Examiner determined that “[o]ne would
have been motivated to do so because of the gene delivery properties of the
virus particles taught in Goldmann et al. and Louboutin et al.” (Id.) The
Examiner also determined that “[t]here is a reasonable expectation of
success that the virus particles would deliver encapsulated gene of interest to
the brain for development of a treatment of Parkinson’s disease.” (Id.)
Regarding the negative limitation of claim 1, the Examiner found that
Louboutin teaches intravenous administration of SV40 VLPs without prior
injection of mannitol resulted in about 3% of all cells expressing the protein,
although there was a tenfold increase in expression with prior intraperitoneal
inoculation with mannitol. (Final Action 7.) The Examiner concluded that
it would have been obvious “to choose from the administration processes
with and without prior mannitol treatment based on experimental needs.
E.g., prior mannitol treatment may need to be avoided if a low level
expression of the transgene is sufficient and potential side effects of
mannitol treatment is undesired.” (Id.)
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We do not agree with the Examiner’s conclusion of obviousness. We
agree with the Examiner that Goldmann indicates that VP1 VLP has
potential as an efficient transporter system for gene therapy because of
efficient binding to B and T cells and kidney cells and internalization to the
nucleus of those cells. However, we disagree with the Examiner that one of
ordinary skill in the art would have had a reasonable expectation of being
able to use the claimed method to treat Parkinson’s disease.
Although Goldmann does indicate that B cells ferry JCV into the
brain, Appellant has provided several prior art references that teach B cells
ferry JCV into the brain when a patient is immunosuppressed. (Appeal Br.
9–11.) In particular, Atwood states: “It has been hypothesized that JCV
gains entry to the brain in B-lymphocytes of immune-suppressed
individuals.” 6 Sabath, published later than Atwood, states: “Upon
immunosuppression, JCV can be reactivated and infect circulating B
lymphocytes. These cells can cross the blood-brain barrier and infect
oligodendrocytes.” 7,8 The Examiner has not established that at the time the

6 Walter J. Atwood et al., Interaction of the Human Polyomavirus, JCV,
with Human B-Lymphocytes, 190 Virology, 716–23, 716 (1992).
7 Bruce F. Sabath and Eugene O. Major, Traffic of JC Virus from Sites of
Initial Infection to the Brain: The Path to Progressive Multifocal
Leukoencephalopathy, 186 (Suppl 2) J. Infect Dis. S180–86, fig. 3 (2002).
8 We also agree with Appellant that Rieckman cited in Goldmann supports
the fact that it was known that JCV is not present in the central nervous
system of normal individuals and thus JCV VL1 VLP would not be expected
to be able to cross the BBB of non-immunosuppressed individuals. (Appeal
Br. 11 (citing Peter Rieckman et al., Regulation of JC Virus Expression in B
Lymphocytes, 68(1) J. Virol., 217–22, 217 (1994) (“[s]ince JCV is not
present in the central nervous system of normal individuals, the virus was
presumed to reside in cells outside of the nervous system, where it remained
dormant until reactivated during periods of immunosuppression. Upon
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Application 16/354,739

8
invention was made that a patient having Parkinson’s disease would have
been believed to be immunocompromised. Thus, even considering Chang,9
a reference the Examiner cited in addressing Appellant’s arguments of non-
obviousness but on which the Examiner did not rely to reject the claims,
which the Examiner argues teaches that “JCV VLPs can be considered as
behaving in a way similar as JCV virus itself in arriving at target sites” (Ans.
10), the Examiner has not established Goldmann provides a basis for a
reasonable expectation of success of using the described JCV VP1 VLP
loaded with a therapeutic protein to treat a patient with Parkinson’s disease.
Although Chang teaches that it should be possible for the JCV VP1 VLPs to
deliver genes into their natural JCV host tissues in humans, it does not teach
or suggest that one would reasonably expect the JCV VLP to cross the BBB
alone without increasing the permeability of the BBB nor does it teach or
suggest the such particle would reasonably be expected to be carried by B
lymphocytes across the BBB in a non-immunosuppressed patient. (See, e.g.,
Chang 1172.) In particular, Chang simply explains that “it has been
demonstrated that VLPs are able to deliver genes into JCV susceptible
tissues for expression since they share similar biological characteristics to
the virion.” (Id.) Subcutaneous delivery in nude mice was shown to deliver
exogenous DNA from the polyoma capsid/DNA complex to “the spleen,
kidneys, parotid gland and liver.” (Id. at 1170.) And Chang indicates in
vitro studies demonstrated that human glioblastoma cells could be infected

reactivation, the cells harboring JCV could cross the blood-brain barrier and
infect glial cells.”)).)
9 Chi-Fang Chang et al., Human JC virus-like particles as a gene delivery
vector, 11(9) Expert Opin. Biol. Ther., 1169–75 (2011).
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with the JC VLP and that VLPs are able to deliver anti-LT siRNA into glial
cell lines transformed by SV40, which cells are then able to inhibit LT
expression and cause apoptosis. (Id. at 1171.) The foregoing does not teach
delivery across the BBB by the JCV VP1 VLP alone10 or by B lymphocytes
in a non-immunosuppressed subject.
In addition, we agree with Appellant that one of ordinary skill in the
art would not have expected the viral vector of Louboutin to be able to be
used to carry a therapeutic protein to treat Parkinson’s disease, without first
administering an additive that decreased the integrity of, or increased the
permeability of, the blood-brain-barrier. In particular, as the Examiner
recognized, in the absence of pretreatment with mannitol, only about 3% of
the cells of the CNS expressed the transgene of the rSV40 vectors.
(Louboutin 905.) The Examiner has provided no evidence that delivery of a
drug to such a small percentage of all the CNS cells would have reasonably
been expected to be able to treat Parkinson’s. Moreover, the Examiner has
not established that the rSV40 vector of Louboutin meets the at least 80%
identity of amino acid sequence SEQ ID NO:1 as required by the claim, or if
modified to so meet the claim, the vector would still work in the same way
described in Louboutin.
Thus, for the foregoing reasons, we reverse the Examiner’s rejection
of claims 1–12 under 35 U.S.C. § 103(a) as unpatentable over Goldmann,
Louboutin, Schulz, and GenBank Accession AAC59325.1

10 Indeed, Chang states that “it is also possible to increase permeability of
the blood-brain barrier (BBB) by some drugs for JCV VLP infection to the
brain cells.” (Id. at 1172.)
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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–12 103(a) Goldmann,
Louboutin, Schulz,
GenBank
Accession
AAC59325.1
1–12

REVERSED