David Szymkowski et al.

Patent Trials and Appeals Board

Dec 17, 2019

14427279 - (D) (P.T.A.B. Dec. 17, 2019)

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.
14/427,279 03/10/2015 David Szymkowski 4500/PCT/US 7753
160212 7590 12/17/2019
SQUIRE PB (SFR Office-IP-2)
275 BATTERY STREET, SUITE 2600
SAN FRANCISCO, CA 94111-3356
EXAMINER
EMCH, GREGORY S
ART UNIT PAPER NUMBER
1649
NOTIFICATION DATE DELIVERY MODE
12/17/2019 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):
IP-Squire@SquirePB.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte DAVID SZYMKOWSKI,
MALU TANSEY, and LESLEY PROBERT

Appeal 2019-000427
Application 14/427,279
Technology Center 1600
____________

BEFORE DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
JOHN E. SCHNEIDER, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The Examiner rejected the claims under 35 U.S.C. § 102 and under
the judicially created doctrine of obviousness-type double patenting.
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 INmune
Bio, Inc. Appeal Br. 1.
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STATEMENT OF THE CASE
Claims 1–3, 7–10, 12, 13, and 18 are pending and stand finally
rejected by the Examiner under 35 U.S.C. § 102(a)(1) and under the
judicially created doctrine of obviousness type double patenting.
A hearing was held November 5, 2019. A transcript of the hearing
will be entered into the record in due course.
Claims 1 and 18 are independent and are reproduced below
(indentations and paragraph breaks have been added for clarity):
1. A method of treating a human patient with neurological
disorder comprising
delivering a therapeutically effective amount of a
dominant negative TNF-α inhibitor polypeptide to the brain of
the human patient by peripherally administering the dominant
negative TNF-α inhibitor polypeptide,
wherein said dominant negative TNF-α inhibitor
polypeptide comprises a variant sequence relative to wild-type
TNF-α and inhibits soluble TNF-α but does not inhibit
signaling by transmembrane TNF-α,
whereby said patient is treated.

18. A method of inhibiting microglial cell activation in a human
patient in need thereof comprising
delivering a therapeutically effective amount of a
dominant negative TNF-α inhibitor polypeptide to the brain of
the human patient by peripherally administering the dominant
negative TNF-α inhibitor polypeptide,
wherein said dominant negative TNF-α inhibitor
polypeptide comprises a variant sequence relative to wild-type
TNF-α and inhibits soluble TNF-α but does not inhibit
signaling by transmembrane TNF-α,
whereby said microglial cell activation is inhibited.

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ANTICIPATION BY DESJARLAIS
Claims 1–3, 7–10, 12, 13, and 18 stand rejected under 35 U.S.C.
§ 102(a)(1) (2013) as anticipated by Desjarlais et al. (WO 2006/113487 A1,
published Oct. 26, 2006) (“Desjarlais”). Ans. 3.
Claims 1 and 18 require delivering a dominant negative TNF-α
inhibitor (“DN-TNF) to the brain by “peripheral administration.” The
Specification discloses that “peripheral administration” means
administration that is not through the cranium or perispinally, and other than
directed administration to the brain. Spec. ¶¶ 6, 91. The Specification
discloses examples of peripheral routes, including, but not limited to,
“enteral, topical, subcutaneous, intradermal, inhalational, parenteral,
intramuscular, mucosal, intra-nasal, oral, vaginal, rectal, intravenous,
intraarterial, intracardiac, intraosseal, intrathecal, intraperitoneal,
intravesical, and intravitreal routes.” Spec. ¶ 6.
The Specification discloses that it was “novel and unexpected finding
that certain dominant negative TNF-α proteins (DN-TNF) have effects on
the CNS and brain when administered peripherally.” Spec. ¶ 6. The
Specification discloses that it was found that the DN-TNF proteins cross the
blood brain barrier (“BBB”) when administered by the peripheral route.
Spec. ¶ 21. The Specification states that the invention “allows for the first
time a method of treating a neurological disorder following peripheral, as
opposed to intracranial, administration of a therapeutic DN-TNF.” Spec.
¶ 22.
The Examiner found that Desjarlais anticipates the claimed invention.
The Examiner found that Desjarlais describes the claimed DN-TNF. Ans. 3.
The Examiner also found that Desjarlais describes treating neurological
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disorders as in claim 1 by peripheral administration. Id. With respect to
claim 18, the Examiner found that microglial activation would be inhibited
upon peripheral administration of DN-TNF and thus would be an inherent
outcome when the protein is administered. Ans. 3–4.
Appellant contends that one of ordinary skill in the art would not have
interpreted Desjarlais to teach peripheral administration of DN-TNF to treat
a neurological disorder because “a person of ordinary skill in the art at the
time the present application was filed would have understood that the BBB
effectively blocks peripherally administered large-molecule therapeutics
from traversing into the brain in therapeutically effective amounts.” Appeal
Br. 8.
The Examiner based the rejection on the following disclosure from
Desjarlais:
FF1.2
Thus, administration of an effective amount of the TNF-α
variants of the present invention may be used to treat these
peripheral nerve injury or demyelinating conditions, as well as
Alzheimer[‘]s disease and Parkinson’s disease.
Desjarlais ¶ 173
FF2.
The administration of the variant TNF-α proteins of the
present invention, preferably in the form of a sterile aqueous
solution, may be done in a variety of ways, including, but not
limited to, orally, subcutaneously, intravenously, intranasally,
transdermally, intraperitoneally, intramuscularly,
intrapulmonary, vaginally, rectally, or intraocularly. In some
instances, for example, in the treatment of wounds,

2 Finding of Fact.
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inflammation, etc., the variant TNF-α protein may be directly
applied as a solution, salve, cream or spray.
Desjarlais ¶ 176.
The Examiner did not identify an express teaching of delivering DN-
TNF to the brain by peripheral administration to treat the neurological
disorders Alzheimer’s disease and Parkinson’s disease (FF1), but rather
relied on the general disclosure of the different routes that DN-TNF can be
administered (FF2). The issue in this rejection is whether the skilled worker
would have recognized that administering DN-TNF by a peripheral route is
effective to treat Alzheimer’s disease and Parkinson’s disease.

Discussion
McCandless3
As evidence that one of ordinary skill in the art would have
understood that Desjarlais teaches that peripherally administered DN-TNF
would penetration the blood brain barrier and reach the brain to treat a
neurological disorder, the Examiner cited McCandless. The Examiner cited
McCandless as teaching that the blood brain barrier is disrupted in multiple
sclerosis which would permit entry of DN-TNF. Ans. 15. Multiple sclerosis
is a neurological disorder. Claim 1 requires treating a neurological disorder.
McCandless teaches:
FF3.
Multiple sclerosis (MS) is an autoimmune disease of the CNS
characterized by disruption of the blood-brain barrier (BBB).

3 Erin E. McCandless et al., IL-1R Signaling within the Central Nervous
System Regulates CXCL12 Expression at the Blood-Brain Barrier and
Disease Severity during Experimental Autoimmune Encephalomyelitis, 183
J. Immunol. 613–620 (2009).
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This breach in CNS immune privilege allows undeterred
trafficking of myelin-specific lymphocytes into the CNS where
they induce demyelination.
McCandless 613 (Abstract)
FF4.
Multiple sclerosis (MS) is believed to be an autoimmune
disease in which myelin-specific CD4+T cells gain excessive
entry to the CNS parenchyma and induce demyelinating disease
(1, 2). The increased trafficking of mononuclear cells during
MS exacerbations is accompanied by blood-brain barrier (BBB)
disruption, as evidenced by the appearance of gadolinium-
enhancing lesions on magnetic resonance imaging (3).
McCandless 613 (column 1) (footnotes omitted).
Although both these passages from McCandless describe disruption of
the BBB, they do not teach what molecules can enter the brain through the
disrupted BBB. Thus, they do not provide persuasive evidence that DN-
TNF could enter through the BBB when administered peripherally as
required by all the rejected claims.
With respect to entry of the lymphocytes through the BBB, as
discussed by Dr. Tansey in the second Tansey declaration (“Tansey 2
Decl.”, executed Sept. 26, 2017), 4 McCandless teaches that “the BBB
‘compromise’ disclosed in McCandless” that permits entry of lymphocytes,
“is primarily a dysregulation of the cell trafficking function (mediated in part
by chemokine expression) of the BBB.” Tansey 2 Decl. ¶ 6. Dr. Tansey’s
statement is supported by the evidence. McCandless further teaches:
FF5.
Under normal conditions, CXCL12 is detected on the
parenchymal surface of the CNS endothelium, where it serves

4 Maria de Lourdes G. Tansey, Ph.D., Professor of Physiology at Emory
University School of Medicine. Tansey 2 Decl. ¶ 1.
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to restrict the entry of infiltrating leukocytes (6–8). This
polarized expression is altered in individuals with CNS
autoimmune diseases with loss of perivascular CXCL12
expression and relocation of the chemokine to the luminal side
of the microvasculature (7, 8). This pathologic pattern of
CXCL12 expression is associated with enhanced activation of
the CXCL12 receptor CXCR4 on infiltrating leukocytes and is
unique to MS and its murine model, experimental autoimmune
encephalomyelitis (EAE) (8). Thus, the altered expression of
CXCL12 at the BBB could promote inappropriate leukocyte
trafficking and contribute to disease pathogenesis.
McCandless 613 (column 1) (emphasis added).
Thus, although McCandless teaches a BBB disruption “allows
undeterred trafficking of myelin-specific lymphocytes into the CNS” (FF1),
this disruption is further explained by McCandless as being related to the
“pathologic pattern of CXCL12 expression” (FF5). For this reason, we
agree with Appellant that McCandless does not provide evidence that one of
ordinary skill in the art would have reason to believe that DN-TNF could
cross the BBB in effective amounts, when administered peripherally as
required by all the claims, to treat multiple sclerosis, a neurological disorder.

Donahue5
The Examiner cited Donahue as evidence that the BBB is “broken
down in Alzheimer’s disease” and therefore would permit entry of DN-TNF
to the brain when administered peripherally. Ans. 16. The following
disclosure is relied upon by the Examiner:

5 John E. Donahue & Conrad E. Johanson, Apolipoprotein E, Amyloid-ß, and
Blood-Brain Barrier Permeability in Alzheimer Disease, 67 J. Neuropathol.
Exp. Neurol. 261–270 (2008).
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FF6.
There is increasing evidence for blood-brain barrier (BBB)
compromise in Alzheimer disease (AD).
Donahue 261.
FF7.
There is growing evidence for BBB compromise in
human AD (13–20) particularly in regions surrounded by Aß
plaques or involved in CAA [cerebral amyloid angiopathy]. In
a recent study of 13 patients who came to autopsy and fulfilled
diagnostic criteria for AD, 4 had physiologic evidence of BBB
impairment, as determined by CSF-albumin index, although
none of these patients had any significant cerebrovascular
disease (18). Therefore, CAA is insufficient as the sole
explanation for BBB impairment in AD. Another recent study
demonstrated perivascular leakage of Aß, complement, and
immunoglobulins in human AD brains (20). This enhanced
permeability can potentially lead to increased deposition of Aß
within AD brains, thereby further worsening the disease (25).
Donahue 262.
Dr. Tansey clarified this disclosure in Donahue by citing Banks6 as
evidence that one of ordinary skill in the art would not have understood
Donahue to teach that DN-TNF would have been expected at the time of the
invention to cross the BBB. Tansey 2 Decl. ¶¶ 9–10. The following
disclosure from Banks is pertinent:
FF8.
Drugs that must reach deep brain targets as is the case in AD
must cross the BBB. However, many drug trials fail because of
inadequate trial design with one of the chief flaws being a
neglect regarding BBB penetration [129]. The BBB represents

6 William A. Banks, Drug delivery to the brain in Alzheimer’s disease:
Consideration of the blood-brain barrier, 64 Advanced Drug Delivery
Reviews, 629-639 (2012) (“Banks”).
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one of the greatest challenges for drug delivery to the CNS and
many strategies have been devised to meet that challenge.
Banks 634 (Section 4).
FF9.
At first it seems obvious that any disruption in the BBB
would improve drug delivery to the brain. This has tempted
many to propose disrupting the BBB for the purposes of drug
delivery, despite the obvious problem that many of the
endogenous substances that will then enter the brain from the
blood are neurotoxic [130]. . . . Studies in stroke models and
with osmotic opening show that the resulting disruption of the
BBB is sufficient to allow therapeutic levels of drug to
accumulate in the disrupted region [131,132]. However, other
studies suggest that the increase in influx rate resulting from
most approaches to BBB disruption is insignificant compared to
the other dynamics that determine the equilibrium between
brain and blood for a solute. . . . The proposed micropunctate
disruptions of the BBB proposed in AD and seen in some
animal models may not be sufficient to allow drugs to reach
therapeutic levels. This is because even a disrupted BBB is
usually still very restrictive in comparison to peripheral tissue
beds. Additionally, the poor diffusion within brain tissue would
prevent drug from reaching areas of the brain more than a few
hundred microns from the lesion. Recently, Cheng et al. found
that BBB disruptions in animal models of AD and multiple
sclerosis were not sufficient to alter small molecule uptake
by brain [53]. Thus, for chronic diseases like AD, current
pharmacologic methods of BBB disruption do not offer an
acceptable cost/benefit ratio for drug delivery.
Banks 634 (Section 4.1) (emphasis added).
FF10.
Paradoxically, disruptions of the BBB could actually
retard the brain retention of some drugs. Even modest
disruptions of the BBB are pathologically significant and
induce inflammatory responses. Tumor necrosis factor-alpha
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can increase Pgp activity leading to a further reduction of
accumulation of Pgp substrates by brain [193–195].
Banks 635 (Section 5.1) (emphasis added).
Banks provides evidence that 1) BBB disruptions would not
necessarily be sufficient to allow a molecule, such as DN-TNF, to cross the
blood barrier; 2) that BBB disruption was not considered acceptable to
deliver drugs (FF9), and 3) might even retard drug delivery (FF10).
Thus, based on the evidence in this record, we agree with Appellant
that one of ordinary skill in the art would not have had reasonable basis to
believe that DN-TNF would necessarily cross BBB in Alzheimer’s disease.

Summary
As discussed in Banks and known in the art, drugs must cross the
BBB to treat a neurological condition, such as multiple sclerosis and
Alzheimer’s disease. However, the BBB is a barrier to the entry of drugs
into the brain (FF6; Tansey 2 Decl. ¶ 3). Thus, the broad teaching in
Desjarlais that DN-TNF can be administered peripherally to treat disease
(FF2) would not have been interpreted by one of ordinary skill in art to mean
the treatment of a neurological disorder involving the brain because the BBB
is a known obstacle to drug entry.
In those neurological diseases with BBB disruptions, one of ordinary
skill in the art also would not interpreted Desjarlais to teach peripheral
administration to reach the brain because the evidence of record as a whole
teaches that such disruptions were not necessarily sufficient to allow an
effective amount of the drug into the brain, and even might retard it (FF5,
FF9, FF10; Tansey 2 Decl. ¶¶ 4–10). Anticipation “may not be established
by probabilities or possibilities. The mere fact that a certain thing may result
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from a given set of circumstances is not sufficient.” In re Robertson, 169
F.3d 743, 745 (Fed. Cir. 1999) (internal citation and quotation marks
omitted).
Accordingly, we conclude that, on this record, the Examiner did not
provide adequate persuasive evidence to establish that Desjarlais anticipates
claims 1–3, 7–10, 12, 13, and 18. The anticipation rejection is reversed.

2. REJECTIONS BASED ON US 7,687,461
Claims 1, 2, 7–10, 12, 13, and 18 stand finally rejected on the ground
of non-statutory obviousness-type double patenting as obvious over claims
1–11 of U.S. Patent No. 7,687,461 B2 (“the ’461 patent”). Ans. 4.
Representative claim 2 of the ’461 patent is reproduced below:
2. A method of treating a Tumor Necrosis Factor-α (TNF-α)
related disorder comprising administering to a patient in need of
said treatment, an effective amount of a composition of a TNF-
α protein comprising an amino acid sequence comprising amino
acid substitutions R31C, C69V.Y87H, C101A and A145R as
compared to the wild type TNF-α sequence of amino acids 1-
157 of SEQ ID NO:13, whereby said TNF-α related disorder is
treated.
The ’461 patent discloses peripheral administration of a TNF protein
(col. 20, ll. 48–50; col. 21, ll. 35–37; col. 52, ll. 22–53), but as found for
Desjarlais, because the BBB is an obstacle to drug penetrance, one of
ordinary skill in the art at the time of the invention would not have
interpreted this disclosure to mean that DN-TNF could be administered
peripherally to treat a neurological disorder in the brain. Accordingly, the
obviousness-type double patenting of claims 1, 2, 7–10, 12, 13, and 18 in
view of the ’461 patent is reversed.

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3. REJECTION BASED ON US 7,687,461 AND TOBINICK
Claims 1–3, 7–10, 12, 13, and 18 stand finally rejected on the ground
of non-statutory obviousness-type double patenting as obvious over claims
1–11 of U.S. Patent No. 7,687,461 B2 and further in view of U.S. Patent No.
6,177,077 B1 (issued Jan. 23, 2001) (“Tobinick”).
Tobinick teaches that TNF plays a central role in the inflammatory
response (col. 1, ll. 61–63). Tobinick also teaches that “TNF has been
shown to have a key role in the central nervous system” (col. 2, ll. 25–26).
Tobinick further teaches “a need for TNF inhibitors” to treat neurological
disorders, that include “multiple sclerosis . . . degenerative disorders of the
nervous system, including Alzheimer’s disease, Parkinson’s disease and
Huntington’s disease.” Tobinick, col. 2, ll. 26–39.
Tobinick further teaches that demyelinating neurological diseases,
“the most important being multiple sclerosis” (col. 7, ll. 42–44), can be
treated intravenously and subcutaneously with etanercept and infliximab
(col. 7, ll. 51–63; col. 11. ll. 34–36). Etanercept is “a recombinant fusion
protein consisting of two soluble TNF receptors joined by the Fc fragment of
a human IgG1 molecule. Tobinick, col. 2, ll. 14–16. Infliximab is an
antibody. Id. at 12–13. Thus, unlike the previously cited prior art, Tobinick
contains express disclosure that a neurological disorder affecting the brain
can be treated by peripheral administration of protein, namely a receptor
protein and antibody.
Claim 1 of Tobinick is directed to “inhibiting the action of TNF for
treating neurological conditions in a human by administering a TNF
antagonist for reducing the inflammation of neuronal tissue.” Dependent
claims 3 and 4 list Alzheimer’s disease and Parkinson’s disease,
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respectively, neurological brain diseases. Thus, claim 1 includes treating
inflammation in Alzheimer’s disease and Parkinson’s disease. Claim 2
recites that the administering “is performed through any of the following
routes: subcutaneous, intravenous, intrathecal, intramuscular, intranasal,
oral, transepidermal, parenteral, by inhalation, or intracerebroventricular.”
The list includes peripheral routes. Therefore, Tobinick also claims that a
neurological brain disorder can be treated by peripheral administration of a
soluble TNF receptor.
Although Tobinick does not disclose peripherally administering the
DN-TNF claimed in the ’461 patent, the teaching that a soluble receptor
protein (claim 1 of Tobinick), a protein fusion, and an antibody can be
administered peripherally to treat a disorder in the brain caused by TNF, and
specifically multiple sclerosis, provides a reasonable basis to believe that
other proteins could cross the BBB, including DN-TNF, making it obvious
to administer it intravenously or subcutaneously.
Appellant argues that it was unexpected that DN-TNF could cross the
BBB, but Appellant did not address the express disclosure in Tobinick of
proteins that are able to traverse it and effectively treat a TNF disorder in the
brain. Appeal Br. 15.
Accordingly, the obviousness-type double-patenting rejection of
Claims 1–3, 7–10, 12, 13, and 18 over the ’461 patent and Tobinick is
affirmed.

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4. REJECTION BASED ON US 7,244,823
Claims 1, 2, 7–10, 12, 13, and 18 stand finally rejected on the ground
of non-statutory double patenting as obvious over claims 1–36 of U.S. Patent
No. 7,244,823 B2 (“the ’823 patent”). Ans. 5.
Representative claim 1 of the ’823 patent is reproduced below:
1. A variant Tumor necrosis factor α (TNF-alpha) protein
comprising an amino acid sequence that has at least one amino
acid substitution in the Large Domain and at least one amino
acid substitution in a domain selected from the group consisting
of the DE Loop and the Small Domain as compared to the wild
type TNF-alpha sequence of amino acids
1–157 of SEQ ID NO:2,
wherein the Large Domain substitution is at a position
selected from the group consisting of 21, 30, 31, 32, 33, 35, 65,
66, 67, 111, 112, 115, 140, 143, 144, 145 and
146,
wherein the Small Domain substitution at a position
selected from the group consisting of 75 and 97,
wherein the DE Loop substitution at a position selected
from the group consisting of 84, 86, 87 and 91, and wherein
said variant TNF-alpha protein is capable of interacting with the
wild type TNF-alpha to form mixed trimers having at least a
50% decrease in receptor activation as compared to a
homotrimer of wild-type TNF-alpha proteins as determined by
a caspase assay.
The ’823 patent discloses peripheral administration of a TNF protein
(col. 17, ll. 26–28; col. 18, ll. 14–16), but as found for Desjarlais, because
the BBB is an obstacle to drug penetrance, one of ordinary skill in the art at
the time of the invention would not have interpreted this disclosure to mean
that DN-TNF could be administered peripherally to treat a neurological
disorder in the brain.
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Accordingly, the obviousness-type double patenting of claims 1, 2, 7–
10, 12, 13, and 18 in view of the ’461 patent is reversed.

5. REJECTION BASED ON US 7,244,823 AND TOBINICK
Claims 1–3, 7–10, 12, 13, and 18 stand finally rejected on the ground
of non-statutory obviousness-type double patenting as obvious over claims
1–36 of U.S. Patent No. 7,244,823 B2 and further in view of Tobinick. Ans.
6.
This rejection over the ’823 patent and Tobinick is affirmed for the
same reasons as the rejection over the ’461 patent and Tobinick (supra at
12–13).

6. REJECTION BASED ON US 7,662,367
Claims 1–3, 7–10, 12, 13, and 18 stand finally rejected on the ground
of non-statutory double patenting as obvious over claims 1–6 of U.S. Patent
No. 7,662,367 B2 (“the ’367 patent”). Ans. 7.
Representative claim 1 of the ’367 patent is reproduced below:
1. A pharmaceutical composition comprising: a variant TNF-α
protein that inhibits the activity of soluble TNF-α while
substantially maintaining the activity of transmembrane TNF-α
comprising an amino acid sequence corresponding to wild type
amino acids 1-157 of Tumor Necrosis Factor Alpha (TNFα)
(SEQ ID NO: 1) that has at least one amino acid substitution in
the Large Domain and at least one amino acid substitution in a
domain selected from the group consisting of the DE Loop and
the Small Domain, wherein the Large Domain substitution is at
a position selected from the group consisting of 21, 30, 31, 32,
33, 35, 65, 66, 67, 111, 112, 115, 140, 143, 144, 145 and 146,
wherein the Small Domain substitution at a position selected
from the group consisting of 75 and 97, wherein the DE Loop
substitution at a position selected from the group consisting of
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84, 87 and 91; a buffer; and, a tonicity agent; wherein said
composition has a pH from approximately 5.0 to 8.0
The ’367 patent discloses peripheral administration of a TNF protein
(col. 7, ll. 18–19; col. 8, ll. 2–4; col. 38, ll. 39–47; col. 39, ll. 33–38; col. 41,
ll. 5–40), but as found for Desjarlais, because the BBB is an obstacle to drug
penetrance, one of ordinary skill in the art at the time of the invention would
not have interpreted this disclosure to mean that DN-TNF could be
administered peripherally to treat a neurological disorder in the brain.
Accordingly, the obviousness-type double patenting of claims 1–3, 7–
10, 12, 13, and 18 in view of the ’367 patent is reversed.

7. REJECTION BASED ON US 7,446,174
Claims 1–3, 7–10, 12, 13, and 18 stand finally rejected on the ground
of non-statutory obviousness-type double patenting obvious over claims 1–
20 of U.S. Patent No. 7,446,174 B2 (“the ’174 patent”). Ans. 7.
Representative claim 1 of the ’174 patent is reproduced below:
1. A method of selectively inhibiting the activity of wild-type
soluble Tumor necrosis factor-α (TNF-α) in a human
comprising administering to said human a molecule that
inhibits the activity of soluble TNF-α substantially maintaining
the activity of transmembrane TNF-α, wherein said molecule is
a variant TNF-α as compared to human wild-type TNF-α (SEQ
ID NO: 12), wherein said TNF-α variant comprises the amino
acid modifications Y87H and A145R or I97T and A145R.

The ’174 patent discloses peripheral administration of a TNF protein
(col. 7, ll. 44–45; col. 9, ll. 2–4; col. 9, ll. 54–56; col. 40, ll. 8–33; col. 41, ll.
20–25), but as found for Desjarlais, because of the BBB, one of ordinary
skill in the art at the time of the invention would not have interpreted this
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disclosure to mean that TNF could be administered peripherally to treat a
neurological disorder of the brain.
Accordingly, for the same reasons the anticipation rejection based on
Desjarlais is reversed, the obviousness-type double patenting rejection of
claim 1–3, 7–10, 12, 13, and 18 over the ’174 patent is reversed.

8. REJECTION BASED ON US 7,642,340 AND TOBINCK
Claims 1–3, 7–10, 12, 13, and 18 stand finally rejected on the ground
of non-statutory obviousness-type double patenting as obvious over claims
1–5 of U.S. Patent No. 7,642,340 B2 (“the ’340 patent) and further in view
of Tobinick.
Representative claim 1 of the ’340 patent is reproduced below:
1. A composition comprising a TNF-α variant monomer, as
compared to SEQ ID NO:3, said variant monomer comprising a
covalently attached polymer at a first amino acid position,
wherein said polymer is attached at a position selected from the
group consisting of 21, 23, 31, 45, 88, 89, 111, 128 and 140,
wherein said variant monomer maintains the ability to exchange
and coassemble with endogenous wild-type TNF-α proteins to
form inactive heterotrimers, and wherein said variant has amino
acid substitutions comprising R31C, C69V and C101 A.
The rejection of claims 1–3, 7–10, 12, 13, and 18 in view of the ’340
patent and Tobinick is affirmed for the same reasons as the rejection over the
’461 patent and Tobinick (supra at 12–13).
.

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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–3, 7–10,
12, 13, 18
102 Desjarlais 1–3, 7–10,
12, 13, 18
1, 2, 7–10,
12, 13, 18
Obviousness-type
double-patenting,
’461 patent
1, 2, 7–10,
12, 13, 18
1–3, 7–10,
12, 13, 18
Obviousness-type
double-patenting,
’461 patent,
Tobinick
1–3, 7–10,
12, 13, 18

1, 2, 7–10,
12, 13, 18
Obviousness-type
double-patenting,
’823 patent
1, 2, 7–10,
12, 13, 18
1–3, 7–10,
12, 13, 18
Obviousness-type
double-patenting,
’823 patent,
Tobinick
1–3, 7–10,
12, 13, 18

1–3, 7–10,
12, 13, 18
Obviousness-type
double-patenting,
’367 patent
1–3, 7–10,
12, 13, 18
1–3, 7–10,
12, 13, 18
Obviousness-type
double-patenting,
’174 patent
1–3, 7–10,
12, 13, 18
1–3, 7–10,
12, 13, 18
Obviousness-type
double-patenting,
’340 patent,
Tobinick
1–3, 7–10,
12, 13, 18

Overall
Outcome
1–3, 7–10,
12, 13, 18

Appeal 2019-000427
Application 14/427,279

19
TIME PERIOD
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