Vikram Arora et al.

Patent Trials and Appeals Board

Jan 14, 2020

12741030 - (D) (P.T.A.B. Jan. 14, 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.
12/741,030 09/14/2010 Vikram Arora DURC044.002APC 3312
20995 7590 01/14/2020
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE, CA 92614
EXAMINER
GOUGH, TIFFANY MAUREEN
ART UNIT PAPER NUMBER
1651
NOTIFICATION DATE DELIVERY MODE
01/14/2020 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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
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PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte VIKRAM ARORA,
MOHAN PAMARTHI, and PHILIP SCUDERI
____________

Appeal 2018-009167
Application 12/741,030
Technology Center 1600
____________

Before DONALD E. ADAMS, JOHN E. SCHNEIDER, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims 1, 14, 19, and 21–30. 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 “Grifols
Therapeutics LLC” (Appellant’s April 12, 2018 Appeal Brief (Appeal Br.)
1).
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STATEMENT OF THE CASE
Appellant’s disclosure “relates to a method for providing alpha-1
antitrypsin (α1-AT) to a subject, in particular a method for providing to the
subject a therapeutically or prophylactically effective amount of α1-AT by a
subcutaneous route” (Spec. 1: 11–13). Appellant’s independent claims 1
and 30 are representative and reproduced below:
1. A method for treating a disorder or disease associated with
α1-AT deficiency in a subject, the method comprising:
administering subcutaneously to the subject in need
thereof a dose of α1-AT, wherein the dose of α1-AT
administered is about 120% of a dose of α1-AT
administered to the subject by intravenous route; wherein
the dose administered by intravenous route achieves a
blood α1-AT trough level of at least about 80 mg/dL;
wherein the amount administered to the subject by
intravenous route is therapeutically effective in
preventing or treating a disorder or disease associated
with α1 AT deficiency;
and
wherein the frequency of α1-AT subcutaneous
administration is sufficient to maintain a trough level of
at least about 80 mg/dL.
(Appeal Br. 20.)
30. A method for treating a disorder or disease associated with
α1 AT deficiency in a subject, the method consisting of:
administering subcutaneously to the subject in need
thereof a dose of α1-AT, wherein the dose of α1-AT
administered is about 120% of a dose of α1-AT
administered to the subject by intravenous route; wherein
the dose administered by intravenous route achieves a
blood α1-AT trough level of at least about 80 mg/dL;
wherein the amount administered to the subject by
intravenous route is therapeutically effective in
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preventing or treating a disorder or disease associated
with α1 AT deficiency;
and
wherein the frequency of α1-AT subcutaneous
administration is sufficient to maintain a trough level of
at least about 80 mg/dL.
(Id. at 21–22.)

Ground of rejection before this Panel for review:
Claims 1, 14, 19, and 21–30 stand rejected under 35 U.S.C. § 103(a)
as unpatentable over the combination of Wewers,2 Piitulainen,3 Barr,4
Shapiro ’958,5 Shapiro ’038,6 Nayar,7 Bookbinder,8 and Favre.9

ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?

2 Wewers et al., Replacement Therapy for Alpha1-antitrypsin Deficiency
Associated with Emphysema, New England Journal of Medicine 1055–1062
(1987).
3 Piitulainen et al., Tailored pharmacokinetic dosing allows self-
administration and reduces the cost of IV augmentation therapy with human
α1-antitrypsin, 59 Eur. J. Clin. Pharmacol. 151–156 (2003).
4 Barr et al., US 2003/0073217 A1, published Apr. 17, 2003.
5 Shapiro, US 7,704,958 B1, issued Apr. 27, 2010.
6 Shapiro, US 6,489,308 B1, issued Dec. 3, 2002.
7 Nayar et al., WO 2005/047323 A1, published May 26, 2005.
8 Bookbinder et al., US 2006/0104968 A1, published May 18, 2006.
9 Favre et al., Hyaluronidase enhances recombinant adeno-associated virus
(rAAV)-mediated gene transfer in the rat skeletal muscle, 7 Gene Therapy
1417–1420 (2000).
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FACTUAL FINDINGS (FF)
FF 1. Wewers discloses that epidemiologic studies resulted in the
identification of an alpha1-antitrypsin (AAT) threshold level of 80 mg per
deciliter, wherein AAT “levels of 50 mg per deciliter or less are associated
with a high risk for the development of emphysema, levels of 50 to 80 mg
per deciliter confer an uncertain risk, and levels above 80 mg per deciliter
confer no increase in risk above the background risk” (Wewers 1057; see
Ans.10 4).
FF 2. Wewers discloses a study wherein the intravenous (IV) infusion of
AAT deficiency patients with “60 mg of active plasma-derived alpha1-
antitrypsin per kilogram of body weight, once a week for up to six months,”
resulted ‘in trough levels above [the] 80 mg per deciliter” threshold (Wewers
1057; see id. at Abstract and 1060; see also Ans. 4).
FF 3. Wewers’ “study demonstrates that weekly intravenous infusions of
alpha1-antitrypsin provide a feasible approach to treating patients with
pulmonary emphysema due to alpha1-antitrypsin deficiency,” wherein
“[i]nfusing 60 mg per kilogram intravenously over 30 minutes once weekly
produced average serum levels of 163 mg per deciliter –– a value more than
twice the level that is thought to protect the lung against injury by proteases”
(Wewers 1060; see id. (Wewers discloses “that intravenous infusion of
alpha1-antitrypsin . . . resulted in a sustained fourfold increase in alpha1-
antitrypsin levels in the lung and a twofold increase in the capacity of the
lung to inhibit neutrophil elastase”); see also Ans. 4).

10 Examiner’s July 27, 2018 Answer.
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FF 4. Piitulainen discloses that severe AAT deficiency predisposes patients
to the development of emphysema and that IV “augmentation therapy with
purified human AAT has been available since 1988,” wherein “[t]he dosage
has varied from 60 mg/kg body weight once weekly to 250 mg/kg once
monthly” (Piitulainen, Abstract; see Ans. 4–5).
FF 5. Piitulainen discloses that the IV administration “of 120 mg/kg every
2 weeks [was] . . . the most convenient for the patients” and concludes that
“[t]he results of [its] study indicate that tailored pharmacokinetic dosing of
human AAT reduces the total annual dose and cost of IV augmentation
therapy” (Piitulainen, Abstract; see id., Title (“Tailored pharmacokinetic
dosing allows self-administration and reduces the cost of IV augmentation
therapy with human α1-antitrypsin”); see also Ans. 4–5).
FF 6. Examiner finds that neither Wewers nor Piitulainen disclose
subcutaneous administration of AAT (Ans. 5).
FF 7. Barr “relates to fusion proteins of protease inhibitors, and to methods
of making and using these fusion proteins, pharmaceutical compositions and
kits comprising these fusion proteins” (Barr ¶ 2; see Ans. 5).
FF 8. Barr “provides fusion proteins of protease inhibitors, or functionally
active portions of protease inhibitors, such as fusion proteins
comprising . . . (AAT) and a second protease inhibitor” (Barr ¶ 10; see Ans.
5).
FF 9. Barr discloses that its “pharmaceutical composition is formulated to
be compatible with its intended route of administration[,]” which may be,
inter alia, IV or subcutaneous (Barr ¶ 112; see Ans. 5).

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FF 10. Barr discloses:
It is understood that the specific dose level for any particular
animal subject will depend upon a variety of factors including
the activity of the specific compound employed, the age, body
weight, general health, gender, and diet of the subject, the time
of administration, the route of administration, the rate of
excretion, any drug combination, and the degree of expression
or activity to be modulated.
(Barr ¶ 124; see Ans. 5.)
FF 11. Barr discloses that “compositions of . . . [its] invention find
particular use in respiratory diseases, such as chronic obstructive pulmonary
diseases (COPD), cystic fibrosis (CF), asthma, and emphysema” (Barr
¶ 139; see Ans. 5).
FF 12. Shapiro ’958 “provides a method of treating an animal suffering a
disease characterized by excessive apoptosis by administering a
therapeutically effective amount of at least one serine protease inhibitor and
thereafter monitoring a decrease in apoptosis. The inhibitor of the invention
includes α1-antitrypsin” (Shapiro ’958, Abstract; see Ans. 6).
FF 13. Shapiro ’958 discloses the “[a]dministration of the therapeutically
effective amount of serine protease inhibitor can be in a bolus, for example,
of about 0.001 to 7 g of α1-antitrypsin-like agent or about 1 to 70 g of a α1-
antitrypsin, per kg of body weight of the subject” (Shapiro ’958 5: 29–35;
see Ans. 6).
FF 14. Shapiro ’958 discloses that the active agent may be administered,
inter alia, IV or subcutaneously (see Shapiro ’958 5: 36–40; see also Ans.
6).
FF 15. Shapiro ’308 discloses:
compositions and methods of blocking diseases associated with
aberrant levels of nitric oxide and facilitated by a serine
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proteolytic (SP) activity are disclosed, which consist of
administering to a subject a therapeutically effective amount of
a compound having a serine protease inhibitory activity.
Among effective compounds are α1-antitrypsin and synthetic
drugs mimicking some or all of the actions of α1-antitrypsin.
(Shapiro ’308, Abstract; see Ans. 6.)
FF 16. Shapiro ’308 discloses that AAT “easily diffuses into tissue spaces
and forms a 1:1 complex with a target protease, principally neutrophil
elastase” (Shapiro ’308 2: 66 – 3: 6; see Ans. 6).
FF 17. Shapiro ’308 discloses “diseases or disorders for which the
therapeutic methods of . . . [its] invention are beneficial include but are not
limited to . . . asthma, . . . [and] chronic obstructive pulmonary disease”
(Shapiro ’308 13: 33–45; see Ans. 6).
FF 18. Shapiro ’308 discloses that its therapeutic agent may be delivered
IV, subcutaneously, or topically (i.e. transdermally), wherein “[t]ransdermal
administration is accomplished by application of a cream, rinse, gel, etc.
capable of allowing the inhibitors of serine proteases to penetrate the skin
and enter the blood stream” and “[p]arenteral routes of administration
include, but are not limited to, direct injection such as intravenous, . . . or
subcutaneous injection” (see Shapiro ’308 17: 31–36 and 18: 14–19; see also
Ans. 6).
FF 19. Nayar “relates to a dry protein formulation, and in particular to a
formulation of alpha1-antitrypsin” (Nayar 1: 3–4; see generally Ans. 6).
FF 20. Nayar discloses that its “dry formulation or, after reconstitution, the
liquid composition is suitable for administration to a patient in need thereof.
Suitable routes of administrations include, but are not limited to, inhalation,
topical, sub-cutaneous and intravenous delivery” (Nayar 4: 26–29; see Ans.
6).
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FF 21. Bookbinder relates
to chemical modifications, pharmaceutical compositions,
expression plasmids, methods for manufacture and therapeutic
methods using . . . [g]lycosaminoglycanases (and domains
thereof and the encoding nucleic acid molecules) for the
therapeutic modification of glycosaminoglycans in the
treatment of disease and for use to increase diffusion of other
molecules such as injected molecules in an animal.
(Bookbinder ¶ 3; see Ans. 6.)
FF 22. Bookbinder discloses that
[t]emporary removal of glycosaminoglycans can be used to
enhance the delivery of solutions and drugs into and/or through
interstitial spaces. This can be useful for the diffusion of
anesthesia and for the administration of therapeutic fluids,
molecules and proteins. Subcutaneous, intradermal and
intramuscular administration of molecules in the presence
of . . . [glycosaminoglycanases] facilitate their systemic
distribution more rapidly. Such methods are very useful when
intravenous access is not available or where more rapid
systemic delivery of molecules is needed. By way of
illustration, delivery of other large molecules such as Factor
VIII, that are poorly bioavailable upon subcutaneous
administration, may be injected with sHASEGPs to increase
their availability.
(Bookbinder ¶ 54; see id. ¶ 59 (Bookbinder discloses that “[i]n the context of
non-intravenous parenteral injections (such as intradermal,
subcutaneous . . . and other injections into spaces other than the vasculature),
a . . . [glycosaminoglycanase in combination with a pharmacologic agent]
can be introduced into a site or sites within the body by injection or
infusion”); see also Ans. 6.)
FF 23. Bookbinder discloses that AAT may be co-administered with
glycosaminoglycanases (Bookbinder ¶ 450; see Ans. 6).
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FF 24. Bookbinder discloses that the dosage of active agent administered
according to its methodology “can be empirically determined by methods
known to those of skill in the art” (Bookbinder ¶ 495; see Ans. 6).
FF 25. Favre discloses that the pretreatment of skeletal muscle with
hyaluronidase, a clinically available enzyme that dissociates the extracellular
matrix, resulted in a consistent and significant increase in the diffusion and
transduction levels of a recombinant adeno-associated virus encoding human
AAT that was injected into the muscle (Favre, Abstract; see Ans. 6–7).
FF 26. Favre discloses that circulating human AAT levels were
“approximately three-fold higher in the hyaluronidase-treated animals than
in sera from the control group” (Favre 1418; see Ans. 6–7).
FF 27. Arora declares that “the finding that about 120% of a therapeutically
effective intravenous dose would deliver a comparable AUC value, blood
trough level, and therapeutic effect, when delivered subcutaneously, would
not have been predicted based on the knowledge at the time the research was
performed” (Arora Decl.11 ¶ 5; see id. ¶ 7 (Arora declares that “[t]here was
nothing in the literature to suggest that a small increase of 20% over an
effective intravenous dose would result in a comparable plasma exposure, as
determined by the Area Under the Curve (AUC), when this increase dose
was given by the subcutaneous route”)).
FF 28. Arora declares that “[a]t the time of invention, little guidance existed
in the literature for determining the subcutaneous dosing of biological
therapeutics” (Arora Decl. ¶ 6 (citing package inserts of “Gamunex

11 Declaration of Vikram Arora, signed April 7, 2017.
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(Grifols),” Declarant’s Exhibit A, and “Hizentra (CSL Behring),”
Declarant’s Exhibit B)).
FF 29. Arora declares that Richter12 “provides evidence of the difficulties
associated with determining subcutaneous doses for biologics and the
challenges associated with developing a subcutaneous administration dosing
regimen” (Arora Decl. ¶ 8).
FF 30. Arora declares that Richter discloses that “‘[s]ubcutaneous
absorption of biotherapeutics is relatively slow and mostly incomplete’
(Abstract), which would direct a researcher attempting to determine the
appropriate subcutaneous dose to consider significantly higher doses for
subcutaneous versus intravenous dosing” (Arora Decl. ¶ 9 (alteration
original); see also id. (Arora declares that Richter’s discussion of “‘potential
species differences are poorly understood,’ ‘presystemic catabolism is
poorly understood,’ and ‘several aspects of subcutaneous absorption are still
poorly understood’” supports Arora’s statement that it was “surprising” that
a subcutaneous administration of an AAT dosage that is “120% of a
reference intravenous dose was efficacious”)).
ANALYSIS
Based on the combination of Wewers, Piitulainen, Barr, Shapiro ’958,
Shapiro ’038, Nayar, Bookbinder, and Favre, Examiner concludes that, at
the time Appellant’s invention was made, it would have been prima facie
obvious to one of ordinary skill in the art to pursue known
options within his or her technical grasp, i.e. used any route of
administration of an AAT formulation disclosed in the art, with

12 Richter et al., Subcutaneous Absorption of Biotherapeutics: Knowns and
Unknowns, 42 Drug Metab. Dispos. 1881–1889 (2014) (Declarant’s Exhibit
C).
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a reasonable expectation for successfully treating disease or
disorders associated with α1-AT deficiency. AAT is disclosed
to be used for subcutaneous administration as well as many
other well-known methods. Dosage regimens for maintaining
AAT trough levels above the threshold levels are known in the
art as is administering AAT at levels which exceed the
protective effect. One of ordinary skill in the art would have a
reasonable expectation of success in determining an amount of
at least 120% of the therapeutically effective amount for
administration to treat a subject having an AAT deficiency
disease because such doses are disclosed by the prior art of
record.
Further, it would have been obvious to one of ordinary
skill in the art to administer hyaluronidase with AAT with a
reasonable expectation for successful subcutaneous
administration because the art teaches that hyaluronidase in
combination with therapeutic molecules facilitates their
systemic distribution more rapidly and promotes dispersion of
the molecule as well as enhancing AAT circulation by three-
fold. Thus, all the claimed elements were known in the prior
art and one skilled in the art could have combined the elements
as claimed by known methods with no change in their
respective functions and the combination would have yielded
predictable results to one of ordinary skill in the art at the time
of the invention.
(Ans. 7; see FF 1–26.)
Examiner and Appellant agree that the combination of Wewers and
Piitulainen does not suggest subcutaneous administration of AAT (see FF 6;
Appeal Br. 5–7).
Barr, Shapiro, and Nayar disclose individually, and in combination,
the subcutaneous administration of AAT (see FF 7–20). Therefore, we are
not persuaded by Appellant’s contention that
Barr, Shapiro, and Nayar . . . cannot cure the failure of Wewers
and Piitulainen to teach or suggest subcutaneous administration
because none of the asserted references actually . . . [exemplify
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subcutaneous administration of AAT, but instead] only list
multiple potential delivery methods for pharmaceutical
compositions and proteins, which amounts to the mention of
subcutaneous delivery out of a laundry list of delivery modes.
(Appeal Br. 7 (emphasis omitted); see also id. at 7–8; cf. Ans. 9.) See In re
Lamberti, 545 F.2d 747, 750 (CCPA 1976) (A reference disclosure is not
limited only to its preferred embodiments, but is available for all that it
discloses and suggests to one of ordinary skill in the art.); see also In re Susi,
440 F.2d 442, 446 n.3 (CCPA 1971) (Disclosed examples and preferred
embodiments do not constitute a teaching away from a broader disclosure or
non-preferred embodiments.); Sinclair & Carroll Co. v. Interchemical
Corp., 325 U.S. 327, 335 (1945) (“Reading a list and selecting a known
compound to meet known requirements is no more ingenious than selecting
the last piece to put into the last opening in a jig-saw puzzle. It is not
invention.”).
We find no evidence on this record to support and, therefore, find
unpersuasive, Appellant’s contention that “one of skill in the art would
readily understand that not all modes of administration [recited in the prior
art relied upon by Examiner] . . . are suitable for all agents contemplated”
(Appeal Br. 8). See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974)
(“Attorney’s argument in a brief cannot take the place of evidence.”).
For the foregoing reasons, we are not persuaded by Appellant’s
contention that “[b]ased only on the disclosure of the cited references, one of
skill in the art . . . would expect the development of subcutaneous
administration to require extensive experimentation, and would not consider
the mere mention of ‘subcutaneous’ to teach subcutaneous administration of
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α1-AT as a viable therapeutic option” (Appeal Br. 9 (emphasis omitted); cf.
FF 7–20).
Wewers makes clear that the effective blood AAT trough level
threshold is above 80 mg/dL (FF 1–3). Piitulainen supports a conclusion
that those of ordinary skill in this art understood how to tailor
pharmacokinetic dosing of human AAT (see generally FF 5). Barr discloses
that those of ordinary skill in this art understood that specific dose levels for
active agents, such as AAT, depends upon a number of factors including the
route of administration (see FF 10; see generally FF 7–11). Shapiro ’308
discloses that AAT “easily diffuses into tissue spaces” (FF 16). In addition,
Shapiro ’958 discloses that AAT may be administered IV or subcutaneously
and that a therapeutically effective amount of a serine protease inhibitor,
such as AAT, ranges from about 0.001 to 7 g per kg of body weight of the
subject (FF 13–14). Therefore, we find no error in Examiner’s conclusion
that it would have been “within the purview of one of ordinary skill in the art
to optimize the subcutaneous dose based upon the knowledge of the artisan
at the time of the claimed invention” (Ans. 15). Stated differently, it would
have been prima facie obvious based on the combination of Wewers,
Piitulainen, Barr, Shapiro ’958, Shapiro ’038, Nayar, Bookbinder, and Favre
to optimize the concentration of AAT administered subcutaneously to, at
least, achieve the art recognized effective blood AAT trough level threshold
of above 80 mg/dL (see FF 1–26; see generally Ans. 9–12). “[W]here[, as
here,] the general conditions of a claim are disclosed in the prior art, it is not
inventive to discover the optimum or workable ranges by routine
experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955).
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Therefore, we are not persuaded by Appellant’s contentions that the
combination of prior art relied upon by Examiner fails to suggest the
“subcutaneous delivery of α1-AT could result in the presently claimed
systemic blood serum trough level” or that by optimizing the subcutaneous
dosage of AAT, to an amount that would produce the art recognized
effective blood AAT trough level threshold, would not have resulted in “a
subcutaneous dose that is about 120% of a therapeutic intravenous dose”
(Appeal Br. 9 (emphasis omitted)).
For the foregoing reasons, we are not persuaded by Appellant’s
contention that Examiner’s conclusion of obviousness is based on
impermissible hindsight (Appeal Br. 10; cf. Ans. 13).
Appellant contends that an FDA transcript13 demonstrates “a long-felt
but unmet need regarding alternative administration routes for α1-AT”
(Appeal Br. 16). Specifically, Appellant contends that
Multiple passages from this transcript confirm the
significance to patients of the inconvenience of intravenous
administration. “It is inconvenient as we will hear from you
requiring regular intravenous administration with package
insert recommending weekly dosing.” Page 29, lines 20-22.
“Now obviously there are also some things that aren’t good
about IV therapy. It’s inconvenient. I have to do it too
frequently. Where it is administered, if that’s a clinic or a
hospital. The cost and access to that therapy.” Page 169, lines
4-8. The preference, based on 70% of respondents, is for
“[o]ral, nasal or sub cute [sic] administration.” Page 173, lines
6-7. The audience voiced a suggestion for a therapy that “we
can give ourselves, we don’t like to have to go to the hospital,

13 Transcript of Proceedings, Public Meeting on Patient-Focused Drug
Development for Alpha-1 Antitrypsin Deficiency, Department of Health and
Human Services, Food and Drug Administration (Sept. 29, 2015).
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or have people come in to give it to use [sic] . . . that we can
actually do ourselves . . . .” Page 204, lines 5-12.
(Appeal Br. 16–17 (alteration original).) In sum, the FDA transcript, as
relied upon by Appellant, asserts: (1) that regular, i.e., weekly, intravenous
administration is inconvenient and costly; (2) a preference for self-
administration; and (3) a preference among 70% of respondents for an oral,
nasal or subcutaneous route of administration (see id.; see also FDA
transcript 29: 20–22, 169: 4–8, 173: 6–7, and 204: 5–12).
Appellant contends that these “passages [from the FDA transcript]
establish the longstanding need . . . for an alternative mode of administration
to the only approved method, that of intravenous infusion” (Appeal Br. 17).
We are not persuaded.
Establishing long-felt need requires objective evidence. See In re
Kahn, 441 F.3d 977, 990 (Fed. Cir. 2009) (“our precedent requires that the
applicant submit actual evidence of long-felt need, as opposed to argument.
This is because ‘[a]bsent a showing of long-felt need or the failure of others,
the mere passage of time without the claimed invention is not evidence of
nonobviousness’” (alteration original)). Furthermore, to establish long-felt
need, Appellant must show: (1) a need has been a persistent one that was
recognized by ordinarily skilled artisans; (2) the long-felt need must not
have been satisfied by another before Appellant’s invention; and (3) the
invention must, in fact, satisfy the long-felt need. In re Gershon, 372 F.2d
535, 538 (CCPA 1967); Newell Co. v. Kenney Mfg. Cos., 864 F.2d 757, 768
(Fed. Cir. 1988); In re Cavanagh, 436 F.2d 491, 496 (CCPA 1971).
Notwithstanding Appellant’s contention to the contrary, only one of
the foregoing passages relates to an alternative to IV administration and this
passage merely asserts a preference among 70% of respondents for an oral,
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nasal, or subcutaneous route of administration (see FDA transcript 173: 6–7;
cf. id. at 29: 20–22, 169: 4–8, and 204: 5–12). Appellant failed to establish
an evidentiary basis on this record to support a finding that a preference
among some portion (i.e. 70% of those who responded to an inquiry) of all
patients receiving AAT administration to treat a disorder or disease
associated with AAT deficiency asserted a preference for a non-IV route of
administration established a long-felt and unresolved need in the field that
was solved by Appellant’s claimed invention.
Nonetheless, on this record, Barr, Shapiro ’958, Shapiro ’038, and
Nayar, each disclose the subcutaneous administration of AAT and, therefore,
satisfy any long-felt need relating to an alternative to IV administration of
AAT (see 7–20).
Further, we note that the evidence relied upon by Examiner
establishes that Pittulainen satisfied any asserted long-felt need, raised in the
remaining passages from the FDA transcript relied upon by Appellant,
specifically the inconvenience and cost associated with weekly IV
administration and a desire for self-administration (see FDA transcript 29:
20–22, 169: 4–8, and 204: 5–12). In this regard, Piitulainen expressly
discloses: “Tailored pharmacokinetic dosing allows self-administration and
reduces the cost of IV augmentation therapy with human α1-antitrypsin,”
wherein Pittulainen “found the dosage of 120 mg/kg every 2 weeks to be the
most convenient for the patients” (FF 5).
Thus, notwithstanding Appellant’s contention to the contrary, the
evidence relied upon by Examiner establishes that Appellant’s asserted long-
felt need was satisfied by others in this art, prior to the date of Appellant’s
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claimed invention (see generally Ans. 17 (Examiner finds that the FDA
transcript “does not present that which is not already known”)).

Claim 1:
For the reasons discussed above, we are not persuaded by Appellant’s
contention
that a person of ordinary skill in the art would not have had any
reasonable expectation of success, nor could have reasonably
predicted, that administering a subcutaneous does of α1-AT that
is about 120% of an intravenous dose would achieve a blood
α1-AT trough level of at least about 80 mg/dL.
(Appeal Br. 10.)
For the foregoing reasons, we are not persuaded by Appellant’s
contention that the combination of prior art relied upon by Examiner fails to
provide a person of ordinary skill in this art with a reasonable expectation of
success or that Examiner’s rationale is conclusory (Appeal Br. 11; see also
Reply Br. 2; cf. Ans. 14–16).
We recognize Appellant’s reference to the Arora Declaration (Appeal
Br. 12; see also id. at 13–14). For the reasons set forth above, we find that
the evidence on this record supports a conclusion that a person of ordinary
skill in this art would have found it prima facie obvious to optimize the
subcutaneous dosage of AAT in order to achieve the art recognized effective
blood AAT trough level threshold. Therefore, we are not persuaded by
Arora’s statements concerning a subcutaneous dosage that is about 120% of
a therapeutically effective intravenous dose (see FF 27).
Further, Arora’s statements concerning the art recognized guidance of
administering AAT subcutaneously and difficulties associated with
subcutaneous administration of biologics are not persuasive in view of the
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weight of the evidence relied upon by Examiner, which supports a
conclusion that it would have been prima facie obvious to subcutaneously
administer AAT to treat a disorder or disease associated with AAT
deficiency in a subject (see FF 28–30; cf. FF 1–29).
Shapiro ’308 discloses that AAT easily diffuses into tissue spaces (FF
16). Therefore, we are not persuaded by Appellant’s unsupported assertion
that “[o]ne of skill in the art would not have expected a large protein such as
α1-AT to have therapeutically useful bioavailability when administered
subcutaneously” (Appeal Br. 13). See In re Pearson, 494 F.2d at 1405
(“Attorney’s argument in a brief cannot take the place of evidence.”). In
addition, we note that Appellant’s claimed method does not exclude the co-
administration of AAT with a reagent, such as a glycosaminoglycanase, to
facilitate the diffusion of a subcutaneously administered active agent into
and/or through a subject’s system to achieve a therapeutic effect within the
scope of Appellant’s claimed invention (see Appeal Br. 20; cf. FF 21–26).
For the foregoing reasons, we are not persuaded by Arora’s
declaration and Appellant’s contention that it was a surprising that a person
of ordinary skill in this art following the guidance provided by the
combination of Wewers, Piitulainen, Barr, Shapiro ’958, Shapiro ’038,
Nayar, Bookbinder, and Favre arrived at an inherently simple method of
providing AAT to a subject (see Appeal Br. 14 (citing Spec. 4: 5–7); see
also FF 30; cf. FF 1–26).

Claim 30:
As discussed above, Shapiro ’308 discloses that AAT easily diffuses
into tissue spaces (FF 16). Thus, a person of ordinary skill in this art would
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have appreciated that the administration of AAT in combination with a
glycosaminoglycanase, such as hyaluronidase, was not required to ensure
that subcutaneously administered AAT will achieve a therapeutic effect
within the scope of Appellant’s claimed invention (see generally Ans. 16–
17).
Therefore, we are not persuaded by Appellant’s contention that the
transitional phrase, “consisting of,” recited in Appellant’s claim 30 excludes
co-administration of AAT with a glycosaminoglycanase, such as
hyaluronidase (see Appeal Br. 15). For the same reasons, we are not
persuaded by Appellant’s contention that “it is particularly surprising that
therapeutic levels were obtained following subcutaneous dosing without co-
administration of hyaluronidase” (id. (emphasis omitted)).

CONCLUSION
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness. The rejection of claims 1 and 30 under
35 U.S.C. § 103(a) as unpatentable over the combination of Wewers,
Piitulainen, Barr, Shapiro ’958, Shapiro ’038, Nayar, Bookbinder, and Favre
is affirmed. Claims 14, 19, and 21–29 are not separately argued and fall
with claim 1.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
1, 14, 19,
21–30
103 Wewers, Piitulainen, Barr,
Shapiro ’958, Shapiro ’038,
Nayar, Bookbinder, Favre
1, 14, 19,
21–30

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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).

AFFIRMED