Lu, Ruying et al.

Patent Trials and Appeals Board

Jan 29, 2020

14115770 - (D) (P.T.A.B. Jan. 29, 2020)

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.
14/115,770 04/10/2014 Ruying Lu 0200.0008-US 5619
39878 7590 01/29/2020
MH2 TECHNOLOGY LAW GROUP, LLP
TIMOTHY M. HSIEH
1951 KIDWELL DRIVE
SUITE 310
TYSONS CORNER, VA 22182
EXAMINER
KISHORE, GOLLAMUDI S
ART UNIT PAPER NUMBER
1612
NOTIFICATION DATE DELIVERY MODE
01/29/2020 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.
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte RUYING LU and RAPHAEL MANNINO
____________

Appeal 2019-005186
Application 14/115,770
Technology Center 1600
____________

Before DONALD E. ADAMS, FRANCISCO C. PRATS, and
MICHAEL A. VALEK, Administrative Patent Judges.

VALEK, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving
claims to cochleate compositions and methods of making such compositions.
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(a). Appellant identifies Matinas Biopharma
Nanotechnologies, Inc. and Rutgers, the State University of New Jersey, as
the real parties in interest. Appeal Br. 4.
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STATEMENT OF THE CASE
The Specification explains that
[c]ochleates are anhydrous, stable, multi-layered lipid crystals
which spontaneously form upon the interaction of
phosphatidylserine and calcium. . . . Cochleate formulations
remain intact in physiological fluids, including mucosal
secretions, plasma and gastrointestinal fluid, thereby mediating
the delivery of biologically active compounds by many routes
of administration, including oral, mucosal and intravenous.
Spec. 1. According to the Specification, “[t]raditionally, such cochleate
formulations have been restricted to the incorporation of hydrophobic active
pharmaceutical ingredients (APIs)” and there is a “need in the art to provide
compositions and methods for making and using cochleate compositions
suitable for the stable and enhanced encochleation of hydrophilic APIs.” Id.
Claims 1, 6, 11, 12, 19, 22, 23, 30–34, 39, 42, 44, 47, 49, 80, 81, 83,
84, and 86 are on appeal and can be found in the Claims Appendix of the
Appeal Brief. Claim 1 is illustrative and reads as follows:
1. A cochleate composition comprising a population of
cochleates, wherein the cochleates comprise:
a) one or more negatively charged first lipids, wherein
the one or more negatively charged first lipids comprise
phosphatidylserine;
b) a cation, wherein the cation is a divalent cation or a
higher valency cation selected from the group consisting of
calcium, zinc, barium, and magnesium cations;
c) a neutral second lipid or group of neutral second
lipids; and
d) a hydrophilic biologically relevant molecule, wherein
the hydrophilic biologically relevant molecule is a drug or an
active pharmaceutical ingredient (API);
wherein the ratio of the one or more negatively charged
first lipids to the neutral second lipid or group of neutral second
lipids is between 1:1 to 9:1; and
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wherein the neutral second lipid or group of neutral
second lipids comprises phosphatidylcholine or a
sphingomyelin.
Appeal. Br., Claims App. i. Appellant agrees that claims 6, 11, 12, 19, 30–
34, 39, 42, 44, 47, 49, 80, 81, 83, and 84 stand or fall with claim 1. Id. at 10.
Claims 22, 23, and 86 are argued separately. Claim 86 is similar to
claim 1, but additionally specifies that “the biologically relevant molecule is
an aminoglycoside.” Id. at Claims App. v. Claim 22 indirectly depends
from claim 1 and reads as follows:
22. The cochleate composition of claim 19, wherein the anti-
infectious agent is an aminoglycoside selected from gentamicin,
netilmicin, tobramycin, amikacin, kanamycin A, kanamycin B,
neomycin, paromycin, neamine, streptomycin,
dihydrostreptomycin, apramycin, ribostamycin, or
spectinomycin.
Id. at ii. Claim 23 depends from claim 22 and recites that the
“aminoglycoside is amikacin.” Id.
Appellant seeks review of the following rejections:2
I. Claims 1, 6, 11, 12, 19, 31–34, 39, 47, 49, 81, 83, and 86 under 35
U.S.C. § 102 as anticipated by Balu-lyer.3
II. Claims 1, 6, 11, 12, 19, 30–34, 39, 42, 44, 47, 49, 80, 81, 83, 84, and
86 under 35 U.S.C. § 103 as unpatentable over Balu-lyer.

2 The obviousness-type double patenting rejection of claims 1, 6, 11, 12, 19,
22, 23, 30–34, 39, 42, 44, 47, 49, 80, 81, 83, 84, and 86 referred to
Examiner’s Answer (see Ans. 15) was withdrawn prior to the appeal in an
Advisory Action mailed January 2, 2019.
3 US 2007/0141135 A1, published June 21, 2007 (“Balu-lyer”).
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III. Claims 1, 6, 11, 12, 19, 22, 23, 30–34, 39, 42, 44, 47, 49, 80, 81, 83,
84, and 86 under 35 U.S.C. § 103 as unpatentable over Gould-
Fogerite,4 Tan,5 Zarif ’894,6 and Zarif ’473.7
IV. Claims 1, 6, 11, 12, 19, 22, 23, 30–34, 39, 42, 44, 47, 49, 80, 81, 83,
84, and 86 under 35 U.S.C. § 103 as unpatentable over Zarif ’473 and
Tan.
V. Claims 33, 34, 39, 42, 44, 47, 49, 80, 81, 83, and 848 under 35 U.S.C.
§ 103 as unpatentable over Gould-Fogerite, Zarif ’894, Zarif ’473,
Tan, Daftary,9 Onyuksel,10 and Balu–lyer.
VI. Claims 1, 6, 11, 12, 19, 22, 23, 30–34, 39, 42, 44, 47, 49, 80, 81, 83,
84, and 86 under 35 U.S.C. § 103 as unpatentable over Zarif ’894,
Zarif ’473, Tan, and Kessler.11
Findings of Fact
FF1. Balu-lyer discloses cochleate compositions “for reducing the
immunogenicity and increasing the circulating half-life of therapeutic
proteins such as Factor VIII.” Balu-lyer, Abstr. These cochleate
compositions comprise “a negatively charged lipid such as
[phosphatidylserine]” and “may also comprise [phosphatidylcholine],” i.e.,

4 US 5,994,318, issued Nov. 30, 1999 (“Gould-Fogerite”).
5 WO 03/082209 A2, published Oct. 9, 2003 (“Tan”).
6 US 6,592,894 B1, issued July 15, 2003 (“Zarif ’894”).
7 US 2003/0219473 A1, published Nov. 27, 2003 (“Zarif ’473”).
8 Both the Appeal Brief (at 9) and Final Action (at 10) list claims 82 and 85
in this rejection. Those claims, however, were cancelled prior to the Final
Action and are not before us now. See Amdt filed May 2, 2018, 11.
9 US 2005/0142178 A1, published June 30, 2005 (“Daftary”).
10 US 6,197,333 B1, issued Mar. 6, 2001 (“Onyuksel”).
11 US 2010/0310541 A1, published Dec. 9, 2010 (“Kessler”).
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an “amphipathic lipid.” Id. ¶¶ 18, 21. Balu-lyer discloses that in some
embodiments “cochleates may . . . comprise 100 mole % of
[phosphatidylserine],” whereas in others “[u]p to 30 mole % of the
[phosphatidylserine] may be replaced by [phosphatidylcholine].” Id. ¶ 29.
FF2. Balu-lyer teaches that “Factor VIII or other proteins or polypeptides
can be associated with (i.e., surface absorbed) or be incorporated into these
structures” because “the proteins associate with the negatively charged
lipids.” Balu-lyer ¶ 20.
FF3. Balu-lyer Example 4 “describes the preparation of
[phosphatidylserine] containing cochleate structures or cylinders.” Balu-lyer
¶ 48. According to this example, an “rFVIII-liposome complex was
generated by incubating concentrated rFVIII solutions in the presence of
liposomes” in a Ca2+ free buffer. Id. Balu-lyer teaches that “[t]he controlled
growth of cochleates cylinders is [then] initiated by spiking Ca2+ ions in the
solution.” Id.
FF4. Gould-Fogerite discloses “cochleates comprising a) a biologically
relevant molecule component b) a negatively charged lipid component, and
c) a divalent cation component.” Gould-Fogerite, Abstr. Gould-Fogerite
teaches
[t]o form cochleate precipitates, a majority of the lipid present
should be negatively charged. One type of lipid can be used or
a mixture of lipids can be used. Phosphatidylserine or
phosphatidylglycerol generally have been used. . . . A
substantial proportion of the lipid can, however, be neutral or
positively charged. The instant inventors have included up to
40 mol % cholesterol based on total lipid present.
Id. at 6:62–7:3.
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FF5. Gould-Fogerite teaches that suitable biologically relevant molecules
for incorporation into such cochleates include polynucleotides as well as
lipophilic drugs and peptides. Gould-Fogerite 2:4–9. According to Gould-
Fogerite, “[b]ecause polynucleotides are hydrophilic molecules and
cochleates are hydrophobic molecules that do not contain an internal aqueous
space, it is surprising polynucleotides can be integrated into cochleates,” (id.
at 8:51–55) but “[a]s demonstrated herein, hydrophilic molecules can be
‘cochleated’, that is, can be made part of the cochleate structure, with little
difficulty.” Id. at 10:12–15.
FF6. Zarif ’894 teaches
[a] process for producing a small-sized, lipid-based cochleate.
Cochleates are derived from liposomes which are suspended in
an aqueous two-phase polymer solution. . . . The liposome-
containing two-phase polymer solution, treated with positively
charged molecules such as Ca2+ or Zn2+, forms a cochleate
precipitate of a particle size less than one micron. The process
may be used to produce cochleates containing biologically
relevant molecules.
Zarif ’894, Abstr.
FF7. Zarif ’894 teaches cochleate compositions comprise “a biologically
relevant molecule,” “a negatively charged lipid,” “a cation component,” and
“may also include minor amounts of zwitterionic lipids, cationic lipids,
polycationic lipids or neutral lipids capable of forming hydrogen bonds to a
biologically relevant molecule.” Id. at 2:33–41, 5:30–33. According to Zarif
’894, the biologically relevant molecule incorporated into its cochleates may
be “hydrophilic, amphiphilic, or hydrophobic in aqueous media” and may be
an “anti-infectious” drug. Id. at 5:55–62.
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FF8. Zarif ’473 describes cochleate compositions comprising “soy
phosphatidylserine” and a “bioactive load.” Zarif ’473, Abstr.12 According
to Zarif ’473, “[t]he bioactive agent/drug (referred to as ‘load’ or drug) can
be hydrophobic in aqueous media, hydrophilic or amphiphilic,” e.g., “a
protein, a small peptide, bioactive polynucleotide,” or “an anti-infectious
agent.” Id. ¶ 46.
FF9. Zarif ’473 teaches cochleates that “are made by using soy
phosphatidylserine in an amount of at least 75% by weight of the lipid
component of the cochleates.” Zarif ’473 ¶ 28. Zarif ’473 further teaches
that these cochleates may include other phospholipids such as
“phosphatidylcholine.” Id. ¶ 29. For example Zarif ’473 recites claims to a
“lipid based cochleate” comprising “at least about 80% by mole soy
phosphatidylserine,” “up to about 20% by mole of a mixture of one or more
lipids other than phosphatidylserine,” selected from a group that includes
“phosphatidylcholine,” and “a multivalent cation.” Id. claims 12, 16.
FF10. Zarif ’473 teaches that cochleates are made by preparing an aqueous
solution of liposomes comprising “at least 75% by weight” soy
phosphatidylserine and “a load of one or more bioactive compounds.” Zarif
’473 ¶¶ 33–34. A multivalent cation such as “Ca++, Zn++ and Mg++” is then
added to form the cochleates. Id. ¶¶ 32, 35.
FF11. Onyuksel describes methods for preparing “biologically active
liposome products comprising a biologically active amphipathic compound in

12 Tan is related to the patent application published as Zarif ’473. Tan
includes the same disclosure that we cite in Zarif ’473 for our findings and
analysis here.

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association with a liposome.” Onyuksel, Abstr. Onyuksel teaches that the
compounds in these liposomes are “peptides which are amphipathic, i.e.,
have both hydrophilic and hydrophobic portions.” Id. at 1:9–12. According
to methods taught in Onyuksel, “a combination of lipids” is mixed to form
liposomes and then incubated with the biologically active compound “under
conditions in which said compound becomes associated with said
liposomes.” Id. at 4:45–58.
FF12. Kessler describes “[c]ompositions and methods for reducing the toxic
effect of certain peptide toxins by administering an agent that directly or
indirectly reduces disulfide bonds that are important for maintaining the toxin
in an active confirmation.” Kessler, Abstr. Kessler teaches that these agents
“can be administered via a nanochochleate or cochleate delivery vehicle.” Id.
¶ 67.
FF13. Kessler teaches that “it can be useful to administer an antibiotic,”
including “[a]minoglycosides (e.g., Amikacin, Gentamicin, Kanamycin,
Neomycin, Netilmicin, Streptomycin, Tobramycin, Paromornycin,
Hygromycin, and Spectinomycin),” together with the “agent for promoting
reduction of disulfide bonds.” Kessler ¶ 34. Kessler teaches that this
“[c]ombination therapy can be achieved by administering two or more
agents, e.g., an agent for reducing toxicity described herein and antibiotic,
each of which is formulated and administered separately, or by administering
two or more agents in a single formulation.” Id. ¶ 37.
Analysis
I. 102 Rejection: Balu-lyer
The issue for this rejection is: Does the preponderance of evidence of
record support Examiner’s determination that Balu-lyer anticipates claims 1,
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6, 11, 12, 19, 31–34, 39, 47, 49, 81, 83, and 86? Claim 1 is representative of
rejected claims 6, 11, 12, 19, 31–34, 39, 47, 49, 81, and 83. We analyze
claim 86 separately.
Claim 1
Examiner finds that Balu-lyer “teaches cochleate formulations
containing an antigen,” i.e., Factor VIII. Final Act. 2. According to
Examiner, Factor VIII is a “hydrophilic biologically relevant molecule,” as
that term is recited in claim 1, because the “instant claims do not define the
hydrophilicity in terms of the molecule having only hydrophilic domains or
the degree of hydrophilicity” and “literature reference show that Factor VIII
and recombinant Factor VIII is soluble in water and buffers.” Final Act. 3.
Examiner determines Balu-lyer discloses Factor VIII cochleate formulations
with “up to 30 mole % of phosphatidylserine” lipid “replaced by
phosphatidylcholine” lipid and, therefore, Balu-lyer discloses cochleates
comprised of the recited negative and neutral lipids within the recited ratio
range. Id. at 2–3; Ans. 10.
Appellant argues that Balu-lyer does not anticipate for two reasons.
First, Appellant argues that it does not sufficiently disclose the invention as
recited in claim 1 because “the only example in Balu-[l]yer of a cochleate
composition is Example 4” and “there is no evidence that cochleates
comprising recombinant Factor VIII were actually prepared.” Appeal Br.
12. Appellant urges that Examiner’s reliance on the “generic teaching” that
“up to 30 mole % of the phosphatidylserine may be replace by
phosphatidylcholine” is misplaced because there is “no specific embodiment
preparing any such cochleate . . . much less a cochleate comprising a
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hydrophilic biologically relevant molecule together with
phosphatidylcholine.” Id. at 13 (internal quotations omitted).
Second, Appellant contends that Balu-lyer “does not teach or suggest
the incorporation of a hydrophilic drug or API into cochleate structures.” Id.
According to Appellant, “it is well-known in the art that most proteins,
including Factor VIII, are not considered purely hydrophilic or hydrophobic
structures.” Id. at 14. Thus, Appellant urges that “even though Factor VIII
does contain hydrophilic amino acids, the Examiner has failed to establish
that Factor VIII is considered a hydrophilic biologically relevant molecule . .
. as claimed herein.” Id. at 15.
Based on the record before us, we determine the preponderance of the
evidence supports Examiner’s anticipation rejection of claim 1. See FF1–
FF3. We agree with, and adopt, Examiner’s findings and reasoning in
support of the rejection of those claims. We are not persuaded by
Appellant’s arguments, which we address below.
We are unpersuaded by Appellant’s argument that Example 4 and the
“generic teaching” in Balu-lyer do not disclose a cochleate composition as
recited in claim 1. See Appeal Br. 12–13. “Anticipation does not require the
actual creation or reduction to practice of the prior art subject matter;
anticipation requires only an enabling disclosure.” Schering Corp. v.
Geneva Pharms., 339 F.3d 1373, 1380 (Fed. Cir. 2003) (citing In re
Donohue, 766 F.2d 531, 533 (Fed. Cir. 1985)). Thus, it is “irrelevant”
whether the cochleates in Example 4 (or any of the other cochleates
described in Balu-lyer) were actually prepared. Id.
Nor is Balu-lyer’s disclosure of cochleate compositions limited to the
particular embodiment in Example 4. Balu-lyer also discloses cochleates
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comprised of phosphatidylserine wherein “[u]p to 30 mole % of the
phosphatidylserine may be replaced by phosphatidylcholine.” FF2. Thus,
Balu-lyer describes cochleate compositions, “arranged or combined in the
same way as recited in the claim,” i.e., comprising a mixture of
phosphatidylserine and phosphatidylcholine at a ratio within the recited
range. See Therasense, Inc. v. Becton, Dickinson & Co., 593 F.3d 1325,
1332 (Fed. Cir. 2010) (quoting Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.
3d 1359, 1371 (Fed. Cir. 2008)).
We are likewise unpersuaded by Appellant’s argument that Factor
VIII is not a “hydrophilic biologically relevant molecule,” as recited in claim
1. See Appeal Br. 13–15. According to Appellant, “it is well-known in the
art that most proteins, including Factor VIII, are not considered purely
hydrophilic or hydrophobic” because they are made up of a multitude of
“amino acids that may individually be considered hydrophilic or
hydrophobic.” Appeal Br. at 14. Thus, Appellant does not dispute
Examiner’s finding that portions of Factor VIII are hydrophilic, thereby
allowing it to “associate with” water. Id.; see also id. at 15 (acknowledging
that “Factor VIII does contain hydrophilic amino acids”).
The issue then is whether, given its broadest reasonable interpretation,
the claim term “hydrophilic biologically relevant molecule” encompasses a
protein, like Factor VIII, that is not “purely” hydrophilic because it also
contains hydrophobic portions; we conclude that it does. Claim 1 does not
recite a “purely” hydrophilic molecule. It does not specify a particular
degree of required hydrophilicity, nor does it otherwise exclude large
molecules with both hydrophilic and hydrophobic domains. To the contrary,
the Specification expressly names “peptides” and “protein” drugs as
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examples of “biologically relevant molecules” that may be incorporated into
cochleates. Spec. 14–15. Indeed, enhanced encochleation of “hydrophilic
molecules or large molecules with hydrophilic domains” is repeatedly
described as the inventors’ purported discovery. Id. at 11, 93 (emphasis
added). Accordingly, we agree with Examiner that the “instant claims do
not define the hydrophilicity in terms of the molecule having only
hydrophilic domains or the degree of hydrophilicity” (Final Act. e) and,
therefore, that Balu-lyer discloses cochleates with a “hydrophilic
biologically relevant molecule” as recited in claim 1.
For these reasons, we affirm the rejection of claim 1 as anticipated by
Balu-lyer. We likewise affirm the rejection of claims 6, 11, 12, 19, 31–34,
39, 47, 49, 81, and 83, which Appellant agrees stand or fall with claim 1.
Claim 86
We reach a different conclusion for claim 86. Claim 86 limits the
“hydrophilic biologically relevant molecule” to an “aminoglycoside.” There
is no evidence that Factor VIII is an aminoglycoside, nor does Examiner
otherwise find that Balu-lyer discloses a “cochleate composition”
comprising an “aminoglycoside” as recited in claim 86. Accordingly, we
reverse the anticipation rejection of claim 86.
II. 103 Rejection: Balu-lyer
The issue for this rejection is: Does the preponderance of evidence of
record support Examiner’s conclusion that claims 1, 6, 11, 12, 19, 30–34, 39,
42, 44, 47, 49, 80, 81, 83, 84, and 86 are obvious over Balu-lyer?
Claim 1
Examiner’s findings for this rejection are substantially the same as
those made for the anticipation rejection over the same reference. See Final
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Act. 13. As before, Appellant argues that “Balu-lyer does not teach or
suggest a hydrophilic drug or API.” Appeal Br. 28.
Based on the record before us, we determine that the preponderance of
the evidence supports Examiner’s rejection of claim 1. See FF1–FF3. We
agree with, and adopt, Examiner’s findings and reasoning in support of that
rejection. We likewise affirm the rejection of claims 6, 11, 12, 19, 22, 23,
30–34, 39, 42, 44, 47, 49, 80, 81, 83, and 84, which Appellant agrees stand
or fall with claim 1. We are not persuaded by Appellant’s argument for the
same reasons discussed above in our analysis of the anticipation rejection.
Claim 86
We reach a different conclusion for separately-argued claim 86.
Examiner has not articulated a rationale to support a finding that the
incorporation of an “aminoglycoside” into a cochleate compositions, as
recited in claim 86, would have been obvious over the teachings in Balu-
lyer. Accordingly, Examiner has failed to establish a prima facie case of
unpatentability for claim 86.
III. 103 Rejection: Gould-Fogerite, Tan, Zarif ’894, and Zarif ’473
The issue for this rejection is: Does the preponderance of evidence of
record support Examiner’s conclusion that claims 1, 6, 11, 12, 19, 22, 23,
30–34, 39, 42, 44, 47, 49, 80, 81, 83, 84, and 86 are obvious over the cited
references? Claim 1 is representative of claims 6, 11, 12, 19, 30–34, 39, 42,
44, 47, 49, 80, 81, 83, and 84. We analyze claims 22, 23, and 86 separately.
Claim 1
Examiner finds that Gould-Fogerite teaches cochleate compositions
that meet all of the limitations of claim 1, including the “neutral second
lipid,” but does “not specifically disclose phosphatidylcholine” or
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sphingomyelin as that neutral lipid. Final Act. 4. Examiner determines that
Zarif ’473 and Tan teach cochleates for the delivery of various biologically
relevant molecules that are formed from phosphatidylserine “in an amount
of at least 75% by weight” and that such compositions may further comprise
“phosphatidylcholine.” Id. at 5–6. Examiner concludes it would be obvious
to use phosphatidylcholine as a neutral lipid to form cochleates taught by
Zarif ’473 and Tan. Id. at 6.
Appellant argues that Examiner has failed to establish a prima facie
case of obviousness because the references fail to disclose a “neutral lipid”
at the ratio recited in claim 1. See Appeal Br. 17–21. In addition, Appellant
relies on Example 5 and Figure 14 of the Specification and the Declaration
of Dr. Mannino, dated June 22, 2017 (“Mannino Decl.”). Id. at 18–20.
Appellant contends this evidence “demonstrates unexpectedly superior
results using the claimed neutral second lipids, phosphatidylcholine and
sphingomyelin, over the use of cholesterol, which is the only second lipid
disclosed in Gould-Fogerite.” Id. at 19.
Based on the record before us, we determine that the preponderance of
the evidence supports Examiner’s rejection of claim 1 over the cited
references. See FF4–FF10. We agree with, and adopt, Examiner’s findings
and reasoning in support of that rejection. We are not persuaded by
Appellant’s arguments, which we address below.
We are unpersuaded by Appellant’s argument that Examiner has
failed to establish a prima facie case of obviousness. All four of the cited
references disclose cochleates comprised of the recited negatively charged
lipid, i.e., phosphatidylserine, and a bivalent cation. And all four references
expressly teach that “hydrophilic” biologically relevant molecules can be
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incorporated into such cochleates. See FF4–FF10. Moreover, Zarif ’473
teaches cochleate compositions comprising a combination of
phosphatidylserine and one of the recited neutral lipids, i.e.,
phosphatidylcholine, at ranges (i.e., 4:1 and 5:1 or greater)13 that overlap
with the “1:1 to 9:1” ratio in claim 1. FF9. This overlap is sufficient to
establish a prima case of obviousness. See In re Peterson, 315 F.3d 1325,
1329 (Fed. Cir. 2003) (“In cases involving overlapping ranges, we and our
predecessor court have consistently held that even a slight overlap in range
establishes a prima facie case of obviousness.”).
Appellant urges that “Zarif ’473 and Tan teach a preferred
embodiment that wholly excludes . . . neutral lipids.” Appeal Br. 21. “But
in 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)). Here, it is clear that Zarif ’473
and Tan also teach embodiments comprising the recited lipids at ratios
within the claimed range. FF9.
Appellant’s argument that Zarif ’893 “teaches away” from the
claimed range because it describes the use of “minor amounts” of neutral
lipids and “only exemplifies a ratio of 100:1” is not persuasive. See Appeal
Br. 18. Zarif ’893 does not provide a numerical range for the “minor

13 Zarif ’473 discloses an amount of phosphatidylserine in terms of both
weight (i.e., “at least 75% by weight of the lipid component”) and moles
(i.e., “at least about 80% by mole”) and teaches that the remainder may be
phosphatidylcholine. FF9. These amounts equate to a ratio of
phosphatidylserine to phosphatidylcholine of 4:1 and 5:1 respectively.
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amounts” of neutral lipids it teaches. See FF6. The 100:1 ratio that
Appellant cites in the Appeal Brief is from one of the examples in Zarif
’893. There is nothing in Zarif ’893 that suggests the ratio in that example is
an upper limit on the amount of neutral lipid, nor does Zarif ’893 otherwise
discourage the use an amount of neutral lipid within the claimed ratio range.
Accordingly, Zarif ’893 does not teach away from claim 1 because it does
not “criticize, discredit, or otherwise discourage investigation into” a ratio of
neutral to negatively charged lipid within the recited range. See Galderma
Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013) (quoting
DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327
(Fed. Cir. 2009)).
Appellant’s evidence of purported unexpected results is insufficient to
overcome Examiner’s prima facie showing of obviousness. The results in
Example 5 report “encapsulation efficiencies” at “99.9% pure PS” and “50%
soy PS” for only two hydrophilic biologically relevant molecules, i.e.,
amikacin and gentamicin. Spec. 94. Figure 14 shows data over a wider
range of ratios, but just for amikacin. Appellant has not demonstrated that
these results are commensurate with the much broader scope of claim 1,
which encompasses any “hydrophilic biologically relevant molecule.”14 See
In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (Evidence of alleged
unexpected results must be “commensurate in scope with the degree of
protection sought by the claims” to demonstrate non-obviousness.). In
addition, Figure 14 shows that the “Percent of Amikacin Encochleated” at

14 The Mannino Declaration refers to Example 5 and Figure 14; it does not
provide any additional data to support Appellant’s unexpected results
argument.
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10% DOPC (dioleoylphosphatidylcholine) is roughly the same as that for
100% DOPS (dioleoylphosphatidylserine). Thus, even if the data were
commensurate with the scope of claim 1, it does not evidence any increase
in encapsulation efficiency at a 9:1 ratio of one of the two recited neutral
lipids––phosphatidylcholine. As such, Appellant has not shown unexpected
results for the entire claimed range. See Peterson, 315 F.3d at 1330–31
(affirming that the prima facie case was not overcome where unexpected
results had not been shown “for the entire claimed range”).
When considered in context of the record as a whole, Appellant’s
evidence does not overcome Examiner’s strong prima facie showing.
Accordingly, we affirm the rejection of claim 1. We likewise affirm the
rejection of claims 6, 11, 12, 19, 30–34, 39, 42, 44, 47, 49, 80, 81, 83, and
84, which Appellant agrees stand or fall with claim 1.
Claims 22, 23, and 86
Examiner states in the Answer that “Zarif teaches aminoglycosides
such as amphotericin B and nystatin,” as recited in claims 22, 23, and 86.
Ans. 12. However, Examiner does not identify any evidence in the record to
support this finding. Moreover, as Appellant points out, this finding is new
in Examiner’s Answer and contradicted by Examiner’s prior determination
that these references do not teach aminoglycosides as active agents. Reply
Br. 3; see, e.g., Final Act. 12 (“What is lacking in [Zarif ’894 and Zarif ’473]
is the teaching of aminoglycosides as the active agents.”). Accordingly,
Examiner has failed to establish a prima facie case of obviousness for claims
22, 23, and 86. We, therefore, reverse the rejection of these claims.
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IV. 103 Rejection: Zarif ’473 and Tan
The issue for this rejection is: Does the preponderance of evidence of
record support Examiner’s conclusion that claims 1, 6, 11, 12, 19, 22, 23,
30–34, 39, 42, 44, 47, 49, 80, 81, 83, 84, and 86 are obvious over the cited
references? Claim 1 is representative of claims 6, 11, 12, 19, 30–34, 39, 42,
44, 47, 49, 80, 81, 83, and 84. We analyze claims 22, 23, and 86 separately.
Claim 1
This rejection is similar to the preceding obviousness rejection. As
before, we determine that the preponderance of the evidence supports
Examiner’s rejection of claim 1 over the cited references. See FF8–FF10.
We agree with, and adopt, Examiner’s findings and reasoning in support of
that rejection. See Final Act. 8–10. We are not persuaded by Appellant’s
arguments, which we address below.
Appellant argues that “read as a whole” Zarif ’473 and Tan “advocate
for the use of hydrophobic material over a hydrophilic one.” Appeal Br. 23.
We disagree. As explained above, these references expressly teach that the
biologically active agent may be “hydrophilic.” FF8.
We are also unpersuaded by Appellant’s argument that Zarif ’473 and
Tan “teach away” from the claimed cochleates because they express a
“preference for 100% phosphatidylserine.” Appeal Br. 23. It is well-settled
that “‘[a] reference does not teach away . . . if it merely expresses a general
preference for an alternative invention.’” Galderma, 737 F.3d at 738
(quoting DePuy, 567 F.3d at 1327). That Zarif ’473 and Tan disclose
preferred embodiments outside the scope of claim 1, does not negate the fact
that it also teaches cochleate compositions as recited in claim 1. See FF8–
FF9; see also Merck 874 F.2d at 807 (explaining that a reference’s
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disclosure of “a multitude of effective combinations does not render any
particular formulation less obvious”). Thus, there is a prima facie showing
that claim 1 is obvious over Zarif ’473 and Tan.
For the same reasons discussed above (see supra § III), Appellant’s
evidence in Example 5 and Figure 14 of the Specification, and in the
Mannino Declaration, is insufficient to overcome Examiner’s prima facie
showing. Accordingly, we affirm the rejection of claim 1. We likewise
affirm the rejection of claims 6, 11, 12, 19, 30–34, 39, 42, 44, 47, 49, 80, 81,
83, and 84, which Appellant agrees stand or fall with claim 1.
Claims 22, 23, and 86
For the same reasons discussed in our analysis of claims 22, 23, and
86 for the ground above (supra § III) Examiner has not established a prima
facie showing of obviousness. Thus, we reverse the rejection of these
claims.
V. 103 Rejection: Gould-Fogerite, Zarif ’894, Zarif ’473, Tan,
Daftary, Onyuksel, and Balu–Iyer
The issue for this rejection is: Does the preponderance of evidence of
record support Examiner’s conclusion that claims 33, 34, 39, 42, 44, 47, 49,
80, 81, 83 and 84 are obvious over the cited references? Claim 33 is
directed to a “method of making the cochleate composition of claim 1”
involving “mixing a hydrophlilic biologically relevant molecule with a
liposome comprising” the recited lipids and adding a divalent cation “to
make the cochleate composition.” Appeal Br., Claims App. iii. Claim 33 is
representative of claims 34, 39, 42, 44, 47, 49, 80, 81, 83 and 84.
Examiner finds that “Daftary [and] Onyuksel each teach the addition
of [an] active agent to the preformed liposomes to load the active agent.”
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Final Act. 11. Examiner determines it would have been obvious in light of
the cited references “to mix the active agent with preformed liposomes to
load the active agent and then add calcium ions to prepare the cochleates
encapsulating the active agent” as recited in claim 33. Id.
Based on the record before us, we determine that the preponderance of
the evidence supports Examiner’s rejection of claim 1 over the cited
references. See FF1–FF11. We agree with, and adopt, Examiner’s findings
and reasoning in support of that rejection. To the extent Appellant repeats
arguments from the other obviousness rejections, we are not persuaded by
those arguments for the reasons discussed above. We address Appellant’s
additional arguments concerning Onyuksel and Daftary below.
Appellant argues that Onyuksel fails “to teach mixing a hydrophilic
biologically relevant molecule with a liposome, which is an express”
limitation of claim 33. Appeal Br. 25. We disagree. Onyuksel teaches the
preparation of liposomes that encapsulate “amphipathic molecules,”
including peptides with both hydrophilic and hydrophobic portions. FF11.
As explained above (supra § I), the broadest reasonable interpretation of the
term “hydrophilic biologically relevant molecule,” as in Appellant’s claims,
includes “large molecules [e.g., peptides] with hydrophilic domains.” See
Spec. 11, 93. Thus, we agree with Examiner that Onyuksel teaches the
preparation of liposomes with a hydrophilic biologically relevant molecule,
as recited in claim 33. See Ans. 14 (“Onyuksel teaches water soluble
peptides and instant claim does not exclude amphipathic peptides which are
also hydrophilic.”).
Moreover, even if Onyuksel did not teach this limitation, the other
references in the cited combination do. Gould-Fogerite, Zarif ’894, Zarif
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’473 each teach the incorporation of “hydrophilic” molecules into cochleate
compositions. See FF5, FF7, and FF8. Moreover, both Zarif ’473 and Balu-
lyer teach the preparation of cochleates by adding a divalent cation to a
solution of liposomes comprising the recited lipids and a hydrophilic
biologically relevant molecule.15 FF3, FF9–10. Appellant cannot overcome
the rejection “by attacking [Onyuksel and Daftary] individually” because
“the rejection is based upon the teachings of a combination of references”
that includes Zarif ’473 and Balu-lyer. See Soft Gel Techs., Inc. v. Jarrow
Formulas, Inc., 864 F.3d 1334, 1341 (Fed. Cir. 2017) (quoting In re Merck
& Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986)).
For these reasons, we affirm the rejection of claim 33. We likewise
affirm the rejection of claims 34, 39, 42, 44, 47, 49, 80, 81, 83 and 84, which
are not argued separately. See 37 C.F.R. § 41.37 (c)(1)(iv).
VI. 103 Rejection: Zarif ’894, Zarif ’473, Tan, and Kessler
The issue for this rejection is: Does the preponderance of evidence of
record support Examiner’s conclusion that claims 1, 6, 11, 12, 19, 22, 23,
30–34, 39, 42, 44, 47, 49, 80, 81, 83, 84, and 86 are obvious over the cited
references? Claim 1 is representative of claims 6, 11, 12, 19, 30–34, 39, 42,
44, 47, 49, 80, 81, 83, and 84. We analyze claims 22, 23, and 86 separately.

15 As explained above, the biologically relevant molecule taught in Balu-
lyer, Factor VIII is within the broadest reasonable interpretation of
“hydrophilic biologically relevant molecule” as recited in Appellant’s
claims. See supra § I.
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Claim 1
We affirm the rejection of claims 1, 6, 11, 12, 19, 30–34, 39, 42, 44,
47, 49, 80, 81, 83, and 84 for the same reasons we affirm the rejection of
those claims as obvious over Zarif ’473 and Tan. See supra § IV.
Claims 22, 23, and 86
Examiner finds “Kessler teaches that drugs such as aminoglycosides
can be encapsulated in cochleates” and therefore it would be obvious to
include an aminoglycoside, as taught in Kessler, in the cochleate
compositions taught in the other references. See Final Act. 12.
Appellant argues that Kessler does not teach that aminoglycosides can
be administered in a cochleate. See Appeal Br. 26–27. According to
Appellant, Kessler references the recited aminoglycosides “only as part of an
exhaustive list of potential antibiotics” that may be used “in combination
therapy” with a different agent, i.e., an “agent for reducing disulfide bonds.”
Id. at 27. Appellant contends there is no teaching “that the antibiotic for use
in [this] combination therapy would or could be encapsulated together with
the agent for reducing disulfide bonds inside of a cochleate structure.” Id.
Based on the record before us, we determine the preponderance of the
evidence supports Examiner’s rejection of claims 22, 23, and 86 as obvious
over the combination of Zarif ’894, Zarif ’473, Tan, and Kessler. See FF6–
FF10, FF12–13. We agree with, and adopt, Examiner’s findings and
reasoning in support of the rejection of these claims. We are not persuaded
by Appellant’s arguments, which we address below.
We are not persuaded by Appellant’s interpretation of Kessler.
Appellant interprets Kessler’s teaching that “the agent can be administered
via a nanocochleate or cochleate delivery vehicle” in paragraph 67 to mean
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that only the agent for reducing disulfide bonds may be “encochleated.”
Appeal Br. 27. But Kessler specifically teaches that antibiotics, including
the aminoglycosides recited in claims 22, 23, and 86, may be together with
that agent “in a single formulation.” FF12. Thus, in addition to teaching
recited aminoglycosides, Kessler reasonably suggests those molecules may
be encapsulated in a cochleate. Kessler’s teachings regarding the particular
antibiotics recited in claims 22, 23, and 86, together with Zarif ’473’s
general teaching that hydrophilic, anti-infectious drugs can be enclosed
within the cochleate compositions it describes (see FF8), are sufficient to
establish a prima facie case of obviousness. Accordingly, we agree
Examiner has met the burden to establish a prima facie case that claims 22,
23, and 86 are obvious over the combination of Zarif ’894, Zarif ’473, and
Tan with Kessler.
Appellant does not present an unexpected results argument, or other
evidence of objective indicia, for this rejection.16 See Appeal Br. 27–28;
Reply Br. 4. Accordingly, we affirm the rejection of claims 22, 23, and 86
based on Examiner’s prima facie showing.
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 6, 11, 12,
19, 31–34,
39, 47, 49,
102 Balu-lyer 1, 6, 11, 12,
19, 31–34,
39, 47, 49,
86

16 We do not consider arguments outside the Appeal Brief. See 37 C.F.R.
41.37(c)(iv). However, we note that the evidence in Example 5, Figure 14,
and the Mannino Declaration does not show unexpected results for the full
range of the ratio recited in claims 22, 23, and 86. See supra § III.
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Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
81, 83, 86 81, 83
1, 6, 11, 12,
19, 30–34,
39, 42, 44,
47, 49, 80,
81, 83, 84,
86
103 Balu-lyer 1, 6, 11, 12,
19, 30–34,
39, 42, 44,
47, 49, 80,
81, 83, 84
86
1, 6, 11, 12,
19, 22, 23,
30–34, 39,
42, 44, 47,
49, 80, 81,
83, 84, 86
103 Gould-Fogerite,
Tan, Zarif ’894,
Zarif ’473
1, 6, 11, 12,
19, 30–34,
39, 42, 44,
47, 49, 80,
81, 83, 84
22, 23, 86
1, 6, 11, 12,
19, 22, 23,
30–34, 39,
42, 44, 47,
49, 80, 81,
83, 84, 86
103 Zarif ’473, Tan 1, 6, 11, 12,
19, 30–34,
39, 42, 44,
47, 49, 80,
81, 83, 84
22, 23, 86
33, 34, 39,
42, 44, 47,
49, 80, 81,
83, 84
103 Gould-Fogerite,
Zarif ’894, Zarif
’473, Tan, Daftary,
Onyuksel
33, 34, 39,
42, 44, 47,
49, 80, 81,
83, 84

1, 6, 11, 12,
19, 22, 23,
30–34, 39,
42, 44, 47,
49, 80, 81,
83, 84, 86
103 Zarif ’894, Zarif
’473, Tan, Kessler
1, 6, 11, 12,
19, 22, 23,
30–34, 39,
42, 44, 47,
49, 80, 81,
83, 84, 86

Overall
Outcome
1, 6, 11, 12,
19, 22, 23,
30–34, 39,
42, 44, 47,
49, 80, 81,
83, 84, 86

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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).

AFFIRMED