Theripion, Inc.

Patent Trials and Appeals Board

Nov 12, 2021

2021000946 (P.T.A.B. Nov. 12, 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.
15/909,314 03/01/2018 Martha S. Hayden-Ledbetter TRP-0120US 1097
10780 7590 11/12/2021
SHERBINA INTELLECTUAL PROPERTY LAW, PLLC
P.O. BOX 3461
REDMOND, WA 98073-3461
EXAMINER
LIU, SAMUEL W
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
11/12/2021 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):
eofficeaction@appcoll.com
nvs@sherbinaiplaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MARTHA S. HAYDEN-LEDBETTER and JEFFREY A.
LEDBETTER

Appeal 2021-000946
Application 15/909,314
Technology Center 1600
Before DONALD E. ADAMS, ULRIKE W. JENKS, and
JAMIE T. WISZ, Administrative Patent Judges.

WISZ, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1–13, 16, 22–24, and 27. 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 Theripion, Inc. as the real party-in-
interest. Appeal Br. 3.
Appeal 2021-000946
Application 15/909,314

2
CLAIMED SUBJECT MATTER
The Specification describes how low levels of high density lipoprotein
(HDL) is associated with increased risk of myocardial infarction. Spec. ¶ 4.
Apolipoprotein A-1 (ApoA-1 or ApoA1) is the principal protein component
of HDL and has become the focus of several HDL-targeted therapeutic
strategies. Id. at ¶ 6. The Specification describes compositions and methods
relating to ApoA-1 fusion polypeptides comprising ApoA1-L1-D, wherein
ApoA-1 is a first polypeptide having cholesterol efflux activity, L1 is a
polypeptide linker, and D is an immunoglobulin Fc region. Id. at ¶¶ 35–37,
305.
Independent claim 1 is illustrative of the claimed subject matter and is
reproduced below:
1. A fusion polypeptide comprising, from an amino-
terminal position to a carboxyl-terminal position, ApoA1-L1-D,
wherein:
ApoA1 is a first polypeptide segment comprising an
amino acid sequence having at least 95% identity with amino
acid residues 19-267 or 25-267 of SEQ ID NO:2, wherein said
first polypeptide segment has cholesterol efflux activity;
L1 is a first polypeptide linker consisting of from 10 to
40 amino acid residues; and D is an immunoglobulin Fc region,
wherein the fusion polypeptide has increased cholesterol
efflux activity as compared to the ApoA1-L1-D fusion
polypeptide in which L1 is a two amino acid linker or is absent.
Appeal Br. 32 (Claims App.).
Appeal 2021-000946
Application 15/909,314

3
REJECTION
The Examiner rejected claims 1–13 and 27 under 35 U.S.C. § 103 as
being unpatentable over Knudsen,2 Benoit,3 Igawa,4 Ledbetter,5 Heusser,6
Nezu,7 Bacus,8 and Lagerstedt,9 as evidenced by Wu.10
The Examiner rejected claims 16 and 22–24 under 35 U.S.C. § 103 as
being unpatentable over Knudsen, Benoit, Igawa, Bacus, Lagerstedt,
Heusser, and Nezu, and further in view of Bielicki ’632,11 Rosenblatt,12 and
Bielicki ’532.13
ISSUES AND ANALYSIS
Rejection of claims 1–13 and 27 under 35 U.S.C. § 103 as being
unpatentable over Knudsen, Benoit, Igawa, Ledbetter, Heusser, Nezu,
Bacus, and Lagerstedt, as evidenced by Wu

2 Knudsen et al., US 2011/0178029 A1, published Jul. 21, 2011
(“Knudsen”).
3 Benoit et al., US 6,258,596 B1, issued Jul. 10, 2001 (“Benoit”).
4 Igawa et al., US 2014/0363428 A1, published Dec. 11, 2014 (“Igawa”).
5 Ledbetter et al., US 8,937,157 B2, issued Jan. 20, 2015 (“Ledbetter”).
6 Heusser et al., US 2012/0121585 A1, published May 17, 2012 (“Heusser”).
7 Nezu et al., US 2014/0112914 A1, published Apr. 24, 2014 (“Nezu”).
8 Bacus et al., US 2009/0318346 A1, published Dec. 24, 2009 (“Bacus”).
9 Lagerstedt et al., US 2015/0353626 A1, published Dec. 10, 2015
(“Lagerstedt”).
10 Wu et al., US 2003/0049694 A1, published Mar. 13, 2003 (“Wu”).
11 Bielicki et al., US 2006/0286632 A1, published Dec. 21, 2006 (“Bielocki
’632”).
12 Rosenblat et al., “Paraoxonose 1 (PON1) enhances HDL-mediated
macrophage cholesterol efflux via the ABCA1 transporter in association
with increased HDL binding to the cells: a possible role for
lysophophatidylcholine,” Artherosclerosis 179 (2005) 69–77 (“Rosenblat”).
13 Bielicki et al., US 2005/0202532 A1, published Sep. 15, 2005 (“Bielicki
’532).
Appeal 2021-000946
Application 15/909,314

4
The Examiner finds that Knudsen teaches a fusion protein wherein
human Apo-A1 is fused at the N-terminus of the Fc portion of an
immunoglobulin by a peptide linker. Final Act. 3–4 (citing Knudsen ¶¶ 13,
68, 674–675, 678). Thus, according to the Examiner, Knudsen teaches the
claimed “ApoA1-L1-D” wherein “L1” is a peptide linker and “D” is the Fc
region. Id. at 4. The Examiner also finds that Knudsen teaches that ApoA-1
promotes cholesterol efflux. Id. (citing Knudsen ¶ 737). The Examiner
acknowledges that Knudsen does not expressly teach the human ApoA-1
amino acid sequence having at least 95% sequence identity to amino acid
residues 19–267 of SEQ ID NO: 2 nor a peptide linker consisting of 10 to 40
amino acids but finds that these limitations are taught by other references.
Id.
The Examiner finds that Benoit teaches that the gene for human
ApoA-1, which is responsible for plasma cholesterol (i.e., cholesterol
efflux), has been cloned. Id. at 4 (citing Benoit :14–29, 1:49–54). The
Examiner further finds that this gene encodes the amino acid sequence of
SEQ ID NO: 2 for human ApoA-1. Id. at 4–5 (showing how amino acid
residues 19–267 of Benoit have 100% sequence identity to amino acid
residues 19–267 of SEQ ID NO: 2).
The Examiner finds that Lagerstedt teaches that the ApoA-1 peptide
can be fused to the Fc fragment of a mammalian antibody, wherein the fused
ApoA-1 peptide has increased plasma half-life as compared to the non-fused
peptide. Id. at 5 (citing Lagerstedt ¶¶ 261, 264–266). The Examiner also
finds that Lagerstedt discloses that the ApoA-1 fusion peptide can include a
peptide linker of 10–50 amino acids, wherein said peptide linker codon is
made up of a majority of amino acids that are sterically unhindered residues
Appeal 2021-000946
Application 15/909,314

5
such as glycine residues, which suggests that a peptide linker with glycine
would be suitable for the fusion of ApoA-1 with an Fc peptide. Id. (citing
Lagerstedt ¶¶ 265–266).
According to the Examiner, Bacus teaches that Gly4Ser3, which is a
glycine rich peptide linker and is non-immunogenic, is a useful linker for
fusion proteins. Id. (citing Bacus ¶ 31, 52). The Examiner also finds that
Bacus teaches that ApoA-1 and Fc peptides can be fusion partners,
“suggesting that the peptide linker ‘(Gly4Ser3)’ is suitable for making fusion
protein comprising ApoA-1 and Fc.” Id. (citing Bacus ¶ 33) (emphasis
omitted). The Examiner also finds that Ledbetter discloses the Gly4Ser3 and
Gly4Ser4 peptide linkers for fusion to the N-terminus of an Fc domain,
wherein use of the Gly4Ser4 linker increased the biological activity of the Fc-
containing fusion protein. Ans. 4 (citing Ledbetter 29:26–27, 30:51–58,
32:46–47, 55:45–52, Fig. 11b).
The Examiner concludes that it would have been obvious to one of
ordinary skill in the art before the filing date of the invention to use human
ApoA-1 to make a fusion protein comprising an Fc peptide and a peptide
linker of 10 to 40 amino acid residues because the sequence was known to
be responsible for plasma cholesterol (i.e., cholesterol efflux) and it was
known that the Fc portion in the fusion protein increases the plasma half-life
of the fused ApoA-1. Final Act. 6. According to the Examiner, the
suggestion to use a peptide linker with sterically unhindered amino acids
such as glycine for the fusion of ApoA-1 is found in Lagerstedt and, in
searching for a glycine-rich peptide linker, one of ordinary skill would have
found the Gly4Ser3 linker of Bacus, which describes this linker as being non-
immunogenic. Id. (citing Bacus ¶¶ 31, 33). The Examiner finds that,
Appeal 2021-000946
Application 15/909,314

6
because the Gly4Ser3 linker is substantially identical in structure to the
claimed linker, the increased ApoA-1 calcium efflux activity of the fusion
peptide is necessarily present. Id. at 7. Thus, the Examiner finds that one of
ordinary skill in the art would have constructed the fusion protein which
comprises ApoA-1, a peptide linker such as Gly4Ser3, and an Fc portion of an
immunoglobulin, in order to treat disorders such as cardiovascular disease
and atherosclerosis with a reasonable expectation of success. Id.
Appellant argues that the Examiner has not identified a reason that
would have prompted a person of ordinary skill in the art to select an
extended linker to join Apo-A1 to the N-terminus of Fc. Appeal Br. 6–21.
Appellant also argues that the Examiner did not properly consider evidence
of unexpected results. Id. at 21–31.
Appellant first asserts that the Examiner has not pointed to any
teachings in the art that would suggest the desirability of using an extended
linker of at least 10 amino acids to fuse ApoA1 to the N-terminus of an Fc
region of an immunoglobulin and that the art fails to teach or suggest any
functional relationship between linker length and protein function in the
context of an ApoA1-Fc fusion. Id. at 8. Appellant also argues that the
teachings in the art relied on by the Examiner to prove motivation to use an
extended linker are considerations that would arise only after a skilled
artisan had already determined that a peptide linker may be needed or
desired for joining ApoA1 and Fc. Id.
We find that the Examiner has the better position. Knudsen teaches a
fusion protein wherein human Apo-A1 is fused to the N-terminus of the Fc
portion of an immunoglobulin and discloses that such fusion may be done
using a peptide linker. Knudsen ¶¶ 13, 68, 674–675, 678. Thus, Knudsen
Appeal 2021-000946
Application 15/909,314

7
teaches that peptide linkers can be used for these fusion proteins and
Appellant’s argument that one of skill in the art would not have been
motivated to use peptide linkers is not persuasive. Further, Lagerstedt
teaches that the ApoA-1 peptide can be fused to the Fc fragment of a
mammalian antibody using a peptide linker of 10–50 amino acids, wherein
the majority of amino acids of the linker are sterically unhindered residues
such as glycine residues. Lagerstedt ¶¶ 264–266. Similarly, Bacus teaches
that the Gly4Ser3 peptide linker is useful for fusion proteins, including
ApoA-1 and Fc (Bacus ¶¶ 31, 33, 52), and Ledbetter teaches the use of a
similar linker (Gly4Ser4) for a Fc fusion protein and also teaches that
incorporation of such a linker increases biological activity of the fusion
partner. See Ledbetter 55:39–59, Fig. 11b. Based on these teachings, we
find that the Examiner has established a prima facie case of obviousness
because one of ordinary skill in the art would have been motivated to include
a linker from 10 to 40 amino acids (such as the Gly4Ser4 linker) in the fusion
peptide taught in Knudsen and would have done so with reasonable
expectation of success in increasing biological activity (i.e., increased
cholesterol efflux activity), as taught in Ledbetter.
Appellant argues that Knudsen does not provide any guidance that
would specifically lead an ordinarily skilled artisan to select a peptide linker
of at least 10 amino acid residues. Appeal Br. 9 (citing Oct. 4, 2018
Declaration of Jeffrey A. Ledbetter under 37 C.F.R. § 1.132 ¶ 9 (“Ledbetter
Declaration”)). However, as discussed above, this teaching is supplied by
the other cited references (e.g., Lagerstedt, Bacus, Ledbetter). “Non-
obviousness cannot be established by attacking references individually
where the rejection is based upon the teachings of a combination of
Appeal 2021-000946
Application 15/909,314

8
references. . . . [The reference] must be read, not in isolation, but for what it
fairly teaches in combination with the prior art as a whole.” In re Merck &
Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Appellant also makes arguments
regarding the disclosures of Bacus and Ledbetter but, similarly, argues the
references individually rather than discussing the prior art in combination.
See Appeal Br. 11–12, 17–18.
Appellant also asserts that “although Lagerstedt discusses linking or
fusing the ApoAl-derived peptide to another molecule such as albumin, a
fatty acid, or an Fc fragment,” it “does not point to or otherwise suggest any
particular reason to use a peptide linker of 10 or more amino acid residues
over a shorter linker or no linker when fusing the ApoAl-derived peptide to
an Fc fragment.” Appeal Br. 10 (citing Lagerstedt ¶ 261; Oct. 20, 2019
Third Declaration of Jeffrey A. Ledbetter under 37 C.F.R. § 1.132 ¶ 9
(“Third Ledbetter Declaration”)). According to Appellant, Lagerstedt does
not include any functional data for an ApoA-1-derived peptide linked to an
Fc region and no such data using longer linkers. Id. As discussed above,
Lagerstedt teaches use of a 10–50 amino acid linker in ApoA1-Fc fragment
fusion peptides and the disclosures of Bacus and Ledbetter further support
this disclosure. The fact that Lagerstedt does not include examples or data
of this embodiment does not negate its disclosure. “[I]n a section 103
inquiry, ‘the fact that a specific [embodiment] is taught to be preferred is not
controlling, since all disclosures of the prior art, including unpreferred
embodiments, must be considered.’” Merck & Co. Inc. v. Biocraft Labs.,
Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (quoting In re Lamberti, 545 F.2d
747, 750 (CCPA 1976)).
Appeal 2021-000946
Application 15/909,314

9
Appellant further contends that the Examiner did not properly
consider evidence of unexpected results. Appeal Br. 21. Appellant points to
Example 1 of the Specification which describes a study that compared the
activity of an ApoA1-Fc protein without a linker with that of ApoA1-Fc
fusions containing either a 2 amino acid linker or a 26 amino acid linker
between ApoA-1 and the Fc region. Id. at 22; Spec. ¶ 248, Fig. 1.
According to Appellant, the results of the study showed that cholesterol
efflux was significantly increased in cultures containing ApoA1-Fc with the
26 amino acid linker compared to either ApoA1-Fc with the 2 amino acid
linker or without a linker. Id. at 22–23 (citing May 23, 2019 Second
Declaration of Jeffrey A. Ledbetter under 37 C.F.R. § 1.132 ¶ 9 (“Second
Ledbetter Declaration”)).
Appellant also presents the results of a separate cholesterol efflux
study in which the activity of six different ApoA1-Fc molecules with linkers
of either 2, 5, 10, 16, 26, or 36 amino acids in length, were compared. Id. at
23 (citing Second Ledbetter Declaration ¶17). According to Appellant,
cholesterol efflux activity of the fusion polypeptides having 10, 16, 26, or 36
amino acid linkers was substantially increased relative to ApoA1-Fc fusion
polypeptides having a 2 amino acid linker. Id. (citing Second Ledbetter
Declaration ¶ 19, Exhibit C). Appellant states that the molecule with a 5
amino acid linker also had significantly more efflux activity than the
molecule with a 2 amino acid linker, although not as much as the
polypeptides with linkers of 10 or more amino acids. Id. Appellant asserts
that these results of superior performance could not have been predicted by
an ordinarily skilled artisan from the cited prior art. Id.
Appeal 2021-000946
Application 15/909,314

10
We are not persuaded that Appellant has provided evidence of
unexpected results that, considered with the prima facie case, supports a
finding of non-obviousness. As discussed above, Bacus teaches that the
Gly4Ser3 peptide linker is useful for fusion proteins, including ApoA-1 and
Fc (Bacus ¶¶ 31, 33, 52), and Ledbetter teaches that incorporation of a
similar linker (Gly4Ser4) in a Fc fusion protein increased the biological
activity of the fusion partner. See Ledbetter 55:39–59; Fig. 11b.
Specifically, Ledbetter compares the biological activity of a Fc fusion
protein with a Gly4Ser4 peptide linker to the activity of a fusion protein
lacking this linker and finds that the incorporation of the linker increases the
biological activity of the fusion partner (a nuclease) compared to the protein
lacking the linker. See id. Ledbetter also teaches that the linker length was
critical in creating a highly active DNase enzyme in the context of the
bispecific nuclease Fc fusion protein. Id. at 55:58. Thus, one of ordinary
skill in the art would similarly expect that use of a peptide linker, such as
Gly4Ser4, would increase the biological activity (i.e., cholesterol efflux
activity) of a Fc fusion protein with ApoA1. “Scientific confirmation of
what was already believed to be true may be a valuable contribution, but it
does not give rise to a patentable invention.” Pharmastem Therapeutics,
Inc. v. Viacell, Inc., 491 F.3d 1342, 1363 (Fed. Cir. 2007).
Therefore, we affirm the Examiner’s rejection of claim 1 as being
unpatentable over Knudsen, Benoit, Igawa, Ledbetter, Heusser, Nezu, Bacus,
and Lagerstedt, as evidenced by Wu. Claims 2–13 and 27 are not argued
separately apart from the independent claim, and, therefore, fall with claim
1. See 37 C.F.R. § 41.37(c)(1)(iv).

Appeal 2021-000946
Application 15/909,314

11
Rejection of claims 16 and 22–24 under 35 U.S.C. § 103 as being
unpatentable over Knudsen, Benoit, Igawa, Bacus, Lagerstedt, Heusser,
Nezu, and further in view of Bielicki ’632, Rosenblatt, and Bielicki ’532
Appellant did not separately argue the Examiner’s rejection of claims
16 and 22–24. Thus, for the same reasons as discussed above, we affirm the
Examiner’s rejection of these claims.
CONCLUSION
For the reasons described herein and those already of record, we
affirm the Examiner’s rejection of claims 1–13, 16, 22–24, and 27.

DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–13, 27 103(a) Knudsen, Benoit,
Igawa, Ledbetter,
Heusser, Nezu,
Bacus, Lagerstedt,
Wu
1–13, 27
16, 22–24 103(a) Knudsen, Benoit,
Igawa, Bacus,
Lagerstedt, Heusser,
Nezu, Bielicki ’632,
Rosenblatt, Bielicki
’532
16, 22–24
Overall
Outcome
1–13, 16,
22–24, 27

Appeal 2021-000946
Application 15/909,314

12
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