Calimmune, Inc. et al.

Patent Trials and Appeals Board

May 11, 2021

2021000147 (P.T.A.B. May. 11, 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.
15/150,373 05/09/2016 Irvin CHEN 12815.0023-00000 5354
22852 7590 05/11/2021
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON, DC 20001-4413
EXAMINER
POPA, ILEANA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
05/11/2021 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):
regional-desk@finnegan.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte IRVIN CHEN, DONG SUNG AN,
MICHELLE MILLINGTON, MAUREEN BOYD,
GEOFFREY P. SYMONDS, and LOUIS RANDALL BRETON

Appeal 2021-000147
Application 15/150,373
Technology Center 1600
____________

Before RICHARD M. LEBOVITZ, JOHN G. NEW, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The Examiner rejected the claims under 35 U.S.C. § 103 as obvious.
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s
decision to reject the claims. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

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 Calimmune,
Inc., and The Regents of the University of California. Appeal Br. 3.
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STATEMENT OF THE CASE
The Examiner rejected claims 18, 25, 27–36, 42, and 44–47 in the
Final Office Action as follows:
Claims 18, 25, 27–33, 36, 42, 44, and 45 under pre-AIA 35 U.S.C.
§ 103(a) as obvious in view of Lois-Caballe et al. (US 2008/0003682 A1,
published Jan. 3, 2008) (“Lois-Caballe”), Egelhofer et al. (J. Virol. 78:568–
575, 2004) (“Egelhofer”). Shen et al. (Nat. Biotechnol., 22:1546–1553,
2004) (“Shen”), and Tremblay et al. (Antimicrob. Agent Chemother.,
49:3483–3485, 2005) (“Tremblay”). Final Act. 2–3
Claims 18, 25, 27–36, 42, and 44–47 under pre-AIA 35 U.S.C.
§ 103(a) as obvious in view of Lois-Caballe, Egelhofer, Shen, Tremblay, and
Ji et al., Mol. Pharmacol. 72:18–28, 2007) (“Ji”). Final Act. 7.
An oral hearing was held April 8, 2021. A transcript of the hearing
will be entered into the record in due course.
Independent claim 18, which is representative of the claimed subject
matter, is copied below:
18. A method of treating or preventing HIV infection in a
patient, comprising administering a pharmaceutical
composition to the patient, the pharmaceutical composition
comprising (i) an expression vector comprising a first nucleic
acid sequence encoding a shRNA having the sequence of SEQ
ID NO: 1, wherein the first nucleic acid is operably linked to an
H1 promoter, and a second nucleic add sequence encoding a
C46 protein that inhibits HIV fusion to a target cell; and (ii) a
pharmaceutically acceptable carrier,
wherein following administration of the pharmaceutical
composition, the immune system to the patient is at least
partially reconstituted with HIV-resistant cells.
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Claim 18 is directed to a method of treating or preventing HIV
infection in a patient. The treatment comprises administering an expression
vector which has two nucleic acids.
The first nucleic acid is a shRNA having the sequence of SEQ ID
NO:1. SEQ ID NO:1 is a sequence complementary to CCR5, an HIV
coreceptor. Spec. ¶¶ 7, 11; Final Act. 3–4. A shRNA is a short hairpin RNA
that, when it has the sequence of SEQ ID NO:1 and is expressed in a cell,
inhibits the expression of CCR5 coreceptor on the surface of the cell. Spec.
¶ 54.
SEQ ID NO:1 is operably linked to an H1 promoter to drive its
expression in the cell into which the vector is introduced. The H1 promoter
is a RNA polymerase III type promoter. Spec. ¶66.
The second nucleic acid encodes the C46 protein. C46 is a peptide
derived from the HIV-1 transmembrane glycoprotein gp41 that inhibits
fusion between gp41 on a target cell and HIV-1. Tremblay 568.
The vector therefore comprises nucleic acids coding for an inhibitor of
the CCR5 coreceptor and an HIV fusion inhibitor. The purpose of the two
inhibitors is to block the entry of HIV into the cells in which the expression
vector is expressed. When both nucleic acids are expressed in a cell, the cell
becomes “HIV-resistant,” namely resistant to the entry of HIV into the cell,
the last requirement of claim 18.

OBVIOUSNESS REJECTIONS
The Examiner found that Lois-Caballe describes treating HIV
infection in a human patient with an expression vector comprising a RNA
polymerase III promoter operably linked to an anti-CCR5 shRNA. Final Act.
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3. The Examiner also found that Lois-Caballe describes decreased
expression of CCR5 in cells which were transformed by anti-CCR5 shRNA
operably linked to the H1 RNA polymerase III promoter. Id. The Examiner
found that the sequence of the anti-CCR5 shRNA described in Lois-Caballe
is identical to SEQ ID NO:1. Id. at 3–4. Thus, Lois-Caballe teaches the first
nucleic acid operably linked to an H1 promoter and inserted into an
expression vector as required by claim 28.
The Examiner also found that Shen describes a lentiviral vector, like
Lois-Caballe, in which an H1 promoter is operably linked to a shRNA and
an IRES expression cassette having two protein-encoding genes to drive
efficient expression of the encoded shRNA and proteins. Final Act. 5.
Therefore, Shen describes using an H1 promoter to express a shRNA in a
cell, albeit not the same shRNA as claimed.
The Examiner found that Lois-Caballe does not describes the vector
comprising a second nucleic acid that codes for the fusion inhibitor C46 as
required by the claim. Final Act. 4. However, the Examiner found that Lois-
Caballe discloses that the expression vector can further comprise a second
nucleic acid coding for a gene of interest. Id. at 3.
The Examiner further cited the disclosure in Egelhofer for the second
nucleic acid encoding C46. Final Act. 4. The Examiner found that Egelhofer
discloses that the C46 nucleic acid, when introduced into cells on a vector,
inhibits HIV entry into the cells. Id. at 4–5. The Examiner stated that it
would have been obvious to one of ordinary skill in the art at the time of the
invention to combine the anti-CCR5 shRNA and nucleic acid encoding C46
on the single vector described in Lois-Caballe to achieve an “efficient anti-
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HIV composition,” namely a CCR5 coreceptor inhibitor and a fusion
inhibitor on the same vector. Id. at 5.
To support the obviousness of the combination, the Examiner cited
Tremblay for its teaching that “the combination between CCR5 inhibitors
and the fusion inhibitor enfuvirtide (T-20) is synergistic.” Final Act. 4.
Enfuvirtide (T-20) and C46 are both variants of gp41.2 The Examiner also
cited Ji in the second rejection for a similar teaching that CCR5 antagonists
and HIV fusion inhibitors are synergistic in inhibiting HIV entry. Id. at 8.
Thus, the Examiner found a reason to place the shRNA encoding SEQ ID
NO: 1 and the C46 on the same vector.

Is there an adequate reason to combine Lois-Caballe and Egelhofer?
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003) and “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).
Appellant argues that the skilled artisan lacked the motivation with a
reasonable expectation of success to have placed the nucleic acid coding for

2 “The C peptides (C36 = DP-178 = T-20 and C34), which are derived from
the C-terminal heptad repeat of the HTV-1 transmembrane glycoprotein
gp41.” Tremblay 568. “Two antiviral C peptides, C36 and C46, both
expressed as membrane-anchored peptides, were compared for antiviral
activity. C36 (also known as DP-178 or T-20) is a 36-aa peptide
corresponding to aa 638 to 673 of HIV . . . gp41. The C46 peptide contains
10 additional amino acids at the N terminus, thus spanning aa 628 to 673 of
gp41.” Tremblay 569.
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C46, as described in Egelhofer, in the expression vector comprising the
shRNA for the CCR coreceptor described by Lois-Caballe. Appeal Br. 8–10.
To support this argument, Appellant cites to the declaration under 37
C.F.R. § 1.132 by Geoffrey P. Symonds, Ph.D., who is also a co-inventor of
the claimed subject matter (“Symonds Decl.”; dated June 28, 2019). Dr.
Symonds has over 30 years of experience “in the fields of gene therapy, viral
vectors, and immunology” (Symonds Decl. ¶ 3) and is acknowledged to be
one of ordinary skill in the art.
We begin by addressing whether the Examiner provided adequate
evidence to establish a reason to place the first and second nucleic acids in
the lentiviral vector described by Lois-Caballe. The reason begins with the
finding that each nucleic acid, the CCR5 shRNA and the C46 nucleic acid,
had been described individually in the cited prior art as useful to treat HIV
infection.
Lois-Caballe discloses that “[t]he inventors have identified shRNA,
such as shRNA hu(1005)(SEQ ID NO: 17) with particular properties that
can be provided to target cells to treat, for example, HIV.” Lois-Caballe
¶ 80. As indicated above, SEQ ID NO:17 is the same sequence as the
claimed sequence and corresponds to a sequence of CCR5. Lois-Caballe also
disclosed delivering the shRNA targeting CCR5 to cells using a lentiviral
vector. Id. ¶¶ 33, 41, 50. Lois-Caballe discloses that the promoter used to
drive expression of the CCR5 shRNA is preferably an RNA polymerase and
lists the H1 promoter as one such promoter. Id. ¶¶ 12, 19. An example is
disclosed in Lois-Caballe of using the H1 promoter to drive expression the
CCR shRNA in cells. Id. ¶ 199.The H1 promoter is the claimed promoter
which drives expression of the shRNA.
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Egelhofer describes a “gene therapeutic strategy targeting entry” of
HIV into cells. Egelhofer, Abstract. Egelhofer used a retrovirus to introduce
nucleic acid coding for C peptides into cells and showed that it inhibited
viral replication in cells. Id. C peptides inhibit HIV entry into cells by
inhibiting fusion of the virus to the cell membrane. Id. at 568 (col. 2). C46 is
a C peptide that was used in Egelhofer’s experiments. Id. at 569 (col. 2).
The concept of using two different anti-HIV therapies, each targeting
a different pathway is described in both Tremblay and Ji. Each of these
publications describe cell-based assays in which cells grown in culture were
challenged with HIV and then treated with various combinations of HIV
inhibitors. Tremblay 3483; Ji 19 (“Material and Methods”). The treatment
was accomplished by adding the drugs to the medium in which the cells
were suspended. Id. The cells were then assayed to determine whether the
drugs inhibited HV from entering the cell. Each of Tremblay and Ji applied
an anti-CCR5 inhibitor and fusion inhibitor to the cells in culture to test their
efficacy as proposed treatments for HIV. These drugs target the same
pathways targeted by the claimed lentiviral vector, and the same inhibitors
described in Lois-Caballe and Egelhofer, respectively. In the claimed
lentiviral vector, the CCR5 shRNA is the anti-CCR5 inhibitor and the C46 is
the HIV fusion inhibitor.
Tremblay discloses: “Combinations of TAK-220 with the fusion
inhibitor enfuvirtide [T-20 and derived from gp41 like the claimed C46]
showed highly synergistic interactions against all viral isolates tested at
every inhibitory concentration used. Tremblay 3484 (col. 2). Tremblay also
discloses that “[t]he interactions of TAK-220 with the fusion inhibitor
enfuvirtide were highly synergistic at these concentrations, as we have
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observed with combinations of some other coreceptor inhibitors and
enfuvirtide in previous studies.” Id. TAK-220 is a small molecule that is a
CCR5 coreceptor antagonist. Tremblay 3483. Enfuvirtide is an HIV fusion
inhibitor. Id. at 3484 (col. 1). Therefore, Tremblay teaches synergy, when
applied to cells, of the same classes of inhibitors coded for by the claimed
lentiviral vector, including a HIV fusion inhibitor related to C46.
Ji described synergy between CCR5 monoclonal antibody antagonists
and the fusion inhibitor enfuvirtide. Ji 18 (Abstract). Thus, like Tremblay, Ji
showed the benefit of using a combination of two drugs, one drug that
inhibits the CCR5 coreceptor and a second drug that is a fusion inhibitor to
inhibit HIV entry into cells.
Based on these teachings of Tremblay and Ji, one of ordinary skill in
the art would have recognized the benefit of using the anti-CCR5 shRNA
described in Lois-Caballe, and the nucleic acid encoding the fusion inhibitor
C46 described in Egelhofer, together as a treatment for HIV.
Dr. Symonds attempts to downplay the teachings in Tremblay and Ji,
by arguing that these publications “merely discuss conventional combination
methods requiring administering two therapeutic agents separately, and
therefore does not teach one to construct a single lentiviral expression vector
targeting two different pathways, for effective treating or preventing HIV
infection in a patient.” Symonds Decl. ¶ 9.
The Examiner is not relying on Tremblay and Ji for teaching the
construction of a vector. It is true that Tremblay and Ji do not provide the
drugs by a lentiviral vector containing nucleic acids encoding the drug as
required by the claim, but rather administer the drugs directly to the cells.
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The two publications, however, provide the reason to target two different
pathways to treat HIV.
The reason to place the CCR5 shRNA and C46 nucleic acid on the
same vector is to achieve their expression in the same cell in an efficient
manner as indicated by the Examiner, rather than on separate vectors where
each vector would have to be taken up by the same cell to achieve local and
concomitant dual expression and treatment of the cells.
Dr. Symonds also states that there would be no reason to place the
C46 gene in Lois-Caballe’s vector because it “only teaches using its ‘gene of
interest’ for viral production and/or detection, which is unrelated to the
inhibition of HIV fusion.” Symonds Decl. ¶ 8.
As discussed by the Examiner, Lois-Caballe’s statement is broader
than Dr. Symonds indicated. Lois-Caballe teaches:
In one embodiment the viral construct further comprises a gene
that encodes a protein that is desirably expressed in one or more
of the target cells, for example, a reporter or marker protein.
Lois-Caballe ¶ 116.
In addition, more than one gene of interest may be placed in
functional relationship with the internal promoter. For example
a gene encoding a marker protein may be placed after the
primary gene of interest to allow for identification of cells that
are expressing the desired protein.
Lois-Caballe ¶ 120.
The “gene of interest” is explicitly described by Lois-Caballe as “a
protein that is desirably expressed in one or more of the target cells.” Lois-
Caballe ¶ 116. A reporter gene is disclosed as an example of desirably
expressed gene, but Lois-Caballe in no way limits the gene of interest to this
example. Although we have considered Appellant’s argument’s to the
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contrary (Reply Br. 3), we do not think it is reasonable to read Lois-Caballe
as limiting a lentivirus vector to being useful for only expression of the
shRNA and a marker gene.
The reporter gene example of Lois-Caballe, in fact, provides the
reason to place a second gene into the Lois-Caballe vector. The reporter
gene is added to the vector when it is desired to gain its expression in the
same cell as the first gene to provide a way of detecting that the vector is
being expressed in the cell. As noted by Dr. Symonds, Lois-Caballe
included the EGFP marker gene in the same lentiviral vector as the shRNA
sequence to serve as the marker to allow for the selection of cells with the
shRNA sequence (“Notably, Lois-Caballe requires the concurrent use of an
EGFP that allows for selecting cells that had been successfully infected by
its viral vector. . . . . In my opinion, the EGFP marker in Lois-Caballe’s viral
vector was indispensable for their shRNA library screen.”). Symonds ¶ 12.
Likewise, to obtain expression of CCR5 shRNA and C46 in the same cell,
for the advantages described in Tremblay and Ji, the skilled worker would
have inserted them into the same vector just as the shRNA and reporter gene
were used in the same vector in Lois-Caballe.
Dr. Symonds states several times in his declaration that the skilled
worker would not have been led to place the CCR5 shRNA and C46 nucleic
acids on the same lentiviral vector. Symonds Decl. ¶¶ 7, 9, 10.
Contrary to Dr. Symonds’s statements, a reason to place two anti-viral
genes on the same vector is described in the cited prior art. Egelhofer
teaches it: “Furthermore, the membrane-anchored peptides are encoded by a
relatively small open reading frame, thus allowing for the expression of
additional antiviral genes in the same vector.” Egelhofer 574 (col. 2). The
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membrane anchored proteins includes C46. Egelhofer 546 (col. 2 in section
titled “The antiviral peptide”). Egelhofer therefore provides additional
reason to have constructed a vector comprising the fusion inhibitor C46 and
the shRNA.
Dr. Symonds states that in his “strong opinion, designing an effective
and safe dual lentiviral expression vector targeting two different pathways
for treating or preventing HIV infection in a patient cannot be based on the
generic information provided by the cited art.” Symonds Decl. ¶ 10. This
statement is not consistent with the facts in this record as a whole. Namely,
the evidence that lentiviral vectors can be used to express two proteins
(Lois-Caballe), the specific teachings that inhibiting two pathways to inhibit
HIV entry into a cell is an effective treatment (Tremblay, Ji), and the
specific teaching in Egelhofer suggesting that C46 expression can be
combined with “additional antiviral genes,” provides strong reason to
combine Lois-Caballe and Egelhofer as the Examiner did. Dr. Symonds
opinion to the contrary is not based on adequate underlying factual findings.

Is there a reasonable expectation of success?
To establish obviousness, there must be a reasonable expectation of
success. In re Merck & Co., Inc., 800 F.2d 1091 (Fed. Cir. 1986). Dr.
Symonds argues that “there is no reasonable expectation of successfully
producing a dual lentiviral expression vector that successfully inhibits or
prevents HIV infection in a patient.” Symonds Decl. ¶ 10. Dr. Symonds
opinion is based on the assertion that the H1 promoter is a “weak promoter”
(id. ¶ 11) and that Lois-Caballe discloses:
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Utilizing weaker promoters to express the small RNA
molecules has been shown to reduce apparent toxicities;
however, the potency of the siRNAs was also attenuated.
Lois-Caballe ¶ 7.
We have considered this argument but are not persuaded it
demonstrates that the Examiner reversibly erred.
First, while Dr. Symonds states that H1 is a weak promoter that would
not be used to express the shRNA to treat HIV infection, he provided no
direct evidence of the strength of the promoter. On the other hand, two
publications cited by the Examiner utilize the H1 promoter to successfully
express shRNA, Lois-Caballe and Shen.
Lois-Caballe teaches:
A variety of pol III promoters can be used with the invention,
including for example, the promoter fragments derived from H1
RNA genes or U6 shRNA genes of human or mouse origin or
from any other species.
Lois-Caballe ¶ 19.
Lois-Caballe uses the H1 RNA polymerase promoter to drive
expression of anti-HIV Rev (a HIV protein) siRNA from a lentiviral in
human cells. Lois-Caballe ¶ 185. Lois-Caballe reported that gene was
expressed in the cells into which it had been introduced that “HIV-1
transcription was significantly suppressed in cells infected with the
recombinant retrovirus comprising the anti-HIV-1 Rev siRNA coding
region.” Id. ¶ 188.
Lois-Caballe also used the H1 promoter to express a “random shRNA
library directed to human CCR5 Sequences.” Lois-Caballe ¶ 199. Lois-
Caballe reported:
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Reduction of CCR5 expression in EGFP+ cells was analyzed at
3 days post infection by monoclonal staining against human
CCR5 (2D7 APC, BD Biosciences) and flow cytometric
analysis. siRNAs were identified by their ability to reduce
CCR5 expression.
Lois-Caballe ¶ 200.
In sum, Lois-Caballe suggests the utility of the H1 promoter to
express anti-HIV agents and describes two experiments in which the
promoter achieved this purpose.
Shen discloses using a vector for expression “of siRNA from H1
promoter.” Shen 1551 (“Methods”). The siRNA down-regulates SOCS1.
Shen 1546. Shen reported that introduction of the vector into cells resulted in
lower SOCS1 expression (“The level of SOCS1 mRNA in the YFP+ LV-
SOCS1-siRNA-DC population was about 90% lower, compared with levels
in mock-transduced DCs.”) Shen 1548.
Despite this evidence, Dr. Symonds states that “the use of H1 in this
context is not applicable to predicting the efficacy of a lentiviral vector for
HIV therapy. Lois-Caballe merely discusses the use of H1 promoter in the
initial shRNA library screen.” Symonds Decl. ¶ 12.
However, as indicated above, the H1 promoter achieves successful
expression of the shRNA in cells, the same objective of HIV therapy – to get
the shRNA expressed in cells at levels at which the CCR5 receptor would be
inhibited and therefore reduce the amount of receptor available for the HIV
to infect the cell. Dr. Symonds does not explain why, achieving the same
objective sought for HIV therapy, but in a cell line, would not be predictive
of the efficacy of the same vector when used in human cells for therapeutic
reasons.
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In sum, Dr. Symonds’ testimony is insufficient to establish the lack of
a reasonable expectation of success to use the H1 promoter to drive
expression of shRNA when three lines of evidence (two from Lois-Caballe
and one from Shen) show that this promoter could successfully express anti-
HIV genes in cells and cause the genes to produce their desired effect on the
cell.
Further to Dr. Symonds testimony, Appellant states:
Rather, in view of the well-established, attenuated potency of
the H1 promoter (see, e.g., Lois-Caballe at paragraph [0007]),
“there would have been no expectation that a lentiviral
expression vector using a weak H1 promoter could drive
sufficient expression of a shRNA to effectively treat or prevent
HIV infection in a patient.” Symonds Declaration at paragraph
11.
Reply Br. 7.
Paragraph 7 of Lois-Caballe says nothing about the “attenuated
potency of the H1 promoter.” There is simply no persuasive, objective
evidence before us that the H1 promoter is weak and would not have been
used for therapeutic purposes, especially in view of three experiments which
show it was effective at expressing RNA in a cell and achieving adequate
levels of the RNA in the cell to reduce expression of the targeted genes.
Appellant’s discussion in the Appeal Brief about the efficacy of the U6
promoter (Reply Br. 8), if anything, supports the rejection because Lois-
Caballe teaches that any RNA polymerase promoter is useful, and U6 is one
of these, providing evidence that members of the genus descried by Lois-
Caballe could be used successfully to express shRNA.
In his declaration. Dr. Symonds also states “absent any data, the
skilled artisan would not have reasonably predicted that a single lentiviral
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expression vector targeting two different pathways could successfully inhibit
or prevent HIV infection in a patient.” Symonds Decl. ¶ 13.
To the contrary, targeting two different pathways involved in HIV
entry was demonstrated by both Tremblay and Ji to inhibit HIV entry better
than each alone, including one pathway involving the same fusion inhibitor
pathway as claimed (T-20 or enfuvirtide, and C46). Thus, once the concept
of using two anti-HIV inhibitors that inhibit the CCR5 co-receptor and HIV
fusion was known in the prior art as established by the Examinerit would
have been reasonably expected by one of ordinary skill in the art that other
ways of administering these drugs would also be effective, such as using a
viral vector as described in Lois-Caballe, Egelhofer, and Shen. Dr. Symonds
did not explain why it would be unpredictable that a lentiviral vector
expressing both CCR5 shRNA and C46 would not be effective at reducing
HIV entry into a cell when the vector would be expected to produce both
these proteins in the same target cell, and therefore achieve the same effect
as in Tremblay and Ji of increasing the local concentrations of the two
inhibitors at the target cell of interest known to inhibit HIV entry. See also
Tremblay 568 (“To overcome these problems, the C36 peptide was
engineered for expression on the cell membrane, leading to a high local
concentration of peptide at the site of action.).
Dr. Symonds also state that that it “may have been the case that the
HIV entry (CCR5 inhibitor) and fusion (C46) would interfere with or impair
one another.” Symonds Decl. ¶ 15. Dr. Symonds did not provide persuasive,
objective evidence for this statement. The evidence provided by the
Examiner rebuts this opinion because each of Tremblay and Ji demonstrate
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that two different HIV agents could be provided to a cell, with not only a
lack of interference, but with a synergistic effect.

Evidence of unexpected results
“One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of ‘unexpected results,’ i.e., to show that
the claimed invention exhibits some superior property or advantage that a
person of ordinary skill in the relevant art would have found surprising or
unexpected.” In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). Appellant cites
to the Specification and Dr. Symond’s declaration as evidence to rebut the
Examiner’s determination that claim 18 would have been obvious to one of
ordinary skill in the art. Appeal Br. 15. Specifically, Dr. Symonds cites
Figure 18 of the Specification which is copied below.

Figure 18, reproduced above, shows an experiment with Mol4/CCR5
cells, which are cells that express the CCR5 coreceptor. The figure shows
six different cell lines, each which was challenged with HIV. The conditions
are as follows: (1) nontransduced Molt4 cells; (2) cells transduced with R5,
the vector comprising the CCR5 shRNA; (3) cells transduced with G2, the
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vector containing the nucleic acid coding for C46; (4) cells transduced with
R5-G2, the vector containing both CCR5 shRNA and C46; (5) cells
transduced with R5-GFP, the vector containing the CCR5 shRNA and the
marker EGFP; and (6) cells (“mix”) transduced with “a mixture of
untransduced, sh5, C46, sh5/C46 all mixed equally (i.e. 25% of each type).”
Spec. ¶ 35. The Specification explains that cells were challenged with HIV
and then the protein levels of the HIV protein p24 was measured after 7 and
10 days as an indicator of HIV infection where the higher levels of p24
indicate higher infection with HIV. Id. ¶¶ 34, 121.
The data in the Specification shows that the reduction in p24 was
greatest for cells transduced with the construct containing both the shRNA
and the C46 nucleic acids. See “R5-G2” in Fig. 18 above. As stated in the
Specification, “[t]he results show that cells expressing the shRNA against
CCR5 and the C46 gene from a single lentiviral construct (dual construct)
provide enhanced protection against infection with a CCR5 tropic HIV strain
at both 7 and 10 days following viral challenge.” Spec. ¶ 121.
Dr. Symonds states that the data in the Specification “showed that
‘cells expressing the shRNA against CCR5 and the C46 gene from a single
lentiviral construct (dual construct) provide enhanced protection against
infection,’ when compared to a ‘mix’ treatment group using individual
therapeutic agents mixed physically.” Symonds Decl. ¶ 17.
This data is insufficient to establish the nonobviousness of the claimed
subject matter. As explained by the Examiner, not all the cells in the “Mix”
(see Fig. 18 above) would necessarily co-express both the shRNA and C46,
the proteins necessary to achieve efficacy against HIV infection because
some cells could take up no vector, or only the R5 vector, or only the G2
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vector, or only the R5-G2 vector (both the shRNA and C46), or
combinations of them. In contrast, there would be fewer possible results
when R5-G2 was used to transduce cells, namely, there would be only cells
that did not take up the vector or those that did. Consequently, Appellant has
not provided persuasive evidence that it would have been surprising that the
R5-G2 experiment was more effective in reducing HIV entry and infection
than the other conditions using both shRNA and C46 (the “Mix”); more cells
would have both inhibitors when only R5-G2 was used as the vector as
compared to when a mix was used to transduce cells where R5-G2 only 25%
of the mix.
The finding that co-expression of both nucleic acids in the same cell
would give better results is scientifically logical. When cells are challenged
with the HIV virus, the presence of one of the inhibitors blocks its entry into
the cell, either by inhibiting the coreceptor or by inhibiting HIV fusion with
the cell. When the same cell expresses both types of inhibitors, then two
different pathways are inhibited and it would be reasonably expected that the
inhibition would be greater than if only one pathway is inhibited. This
expectation is based on the synergy described in both Tremblay and Ji
showing a better result when both a CCR inhibitor and a HIV fusion
inhibitor were used on the same cells in comparison to either inhibitor alone.
These publications showed a better result when both inhibitors were co-
administered and available at the same time to the same cell, just as would
occur when the dual vector is transduced into one cell.
Dr. Symonds also cites journal articles which Dr. Symonds states
“demonstrated the superior efficacy of the claimed dual lentiviral expression
vector for inhibiting or preventing HIV infection.” Symonds Decl. ¶ 14.
Appeal 2021-000147
Application 15/150,373

19
Burke, Peterson, and Symonds teach that the lentiviral vector expressing
CCR5 shRNA and C46 provide significant protection from HIV infection.
Id. Ledger teaches that the anti-CCR5 shRNA and C46 do not interfere with
one another. Id. For the reason explained above, it would have been
expected that expressing both inhibitors at the same time in the same cell
would provide the best protection against HIV infection because both
pathways are blocked, an expectation confirmed by each of Tremblay and Ji.
It has not been adequately explained on this record why the teaching in
Tremblay and Ji is not applicable when, just as a dual lentiviral vector, they
achieve local concentrations of the inhibitors that are available to block HIV
entry into the cell.
For the foregoing reasons, the obviousness rejection of claim 18 is
affirmed. Claims 25, 27–36, 42, and 44–47 were not argued separably and
fall with claim 18. 37 C.F.R. § 41.37(c)(1)(iv).

CONCLUSION
In summary:
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
18, 25, 27–
33, 36, 42,
44, 45
103 Lois-Caballe,
Egelhofer, Shen,
Tremblay
18, 25, 27–
33, 36, 42,
44, 45

18, 25, 27–
36, 42, 44–
47
103 Lois-Caballe,
Egelhofer, Shen,
Tremblay, Ji
18, 25, 27–
36, 42, 44–
47

Overall
Outcome
18, 25, 27–
36, 42, 44–
47

Appeal 2021-000147
Application 15/150,373

20

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)(1)(iv)(2019).

AFFIRMED