Ex Parte Farokhzad et al

Patent Trial and Appeal Board

May 3, 2018

12515465 (P.T.A.B. May. 3, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/515,465 05/05/2010
23579 7590 05/04/2018
Pabst Patent Group LLP
1545 PEACHTREE STREET NE
SUITE 320
ATLANTA, GA 30309
FIRST NAMED INVENTOR
Omid C. Farokhzad
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
MIT 12477 9774
EXAMINER
DAHLE, CHUN WU
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
05/04/2018 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte OMID C. F AROKHZAD, FRANK ALEXIS, TIMOTHY T. KUO,
ERIC PRIDGEN, ALEKSANDAR FILIP RADOVIC-MORENO, and
ROBERTS. LANGER1
Appeal2017-001466
Application 12/515,465
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, and RYAN H. FLAX,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to
nanoparticles for delivery of an active agent, which have been rejected as
lacking adequate written description, nonenabled, and obvious. We have
jurisdiction under 35 U.S.C. § 6(b ).
We reverse both rejections under 35 U.S.C. § 112, first paragraph, but
affirm the rejections for obviousness.
1 Appellants identify the Real Parties in Interest as Massachusetts Institute of
Technology; The Brigham and Women's Hospital, Inc.; and Bind
Biosciences, Inc. (Appeal Br. 3.)
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Application 12/515,465
STATEMENT OF THE CASE
"The FcRn receptor molecule is well characterized. The FcRn
receptor binds IgG (but not other immunoglobulin classes such as IgA, IgD,
IgM, and/or IgE) at acidic pH and not at basic pH. FcRn transports IgG
across epithelial cells." Spec. ,r 5. "FcRn binding partners include whole
IgG, the F c fragment of IgG, and/ or other fragments of IgG that include the
complete binding region for the FcRn receptor." Id.
"The present invention relates to F cRn binding partners for the
targeted delivery of vaccines, antigens, drugs, therapeutics, microparticles,
nanoparticles, picoparticles, etc. to and/or across epithelial and/or
endothelial barriers." Id. "By using FcRn targeted nanoparticles, it may be
possible to enhance delivery across cells, layers of cells, and/or tissues,
resulting in improved drug distribution and targeting." Id.
Claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, 114, 115, and 117
are on appeal. Claim 1 is illustrative and reads as follows:
1. A polymeric nanoparticle having a size in the range of 10 to 500
nm, compnsmg
an F cRn binding partner comprising an IgG F c fragment at least 80%
homologous to SEQ ID No.: 1, wherein the Fe fragment includes a complete
binding region to an FcRn receptor, and wherein the binding partner is
present on the surface of the nanoparticle and binds to an FcRn receptor to
cause transcytosis of the nanoparticle through a cell layer, and a therapeutic,
diagnostic, prognostic, or prophylactic agent for delivery into an interstitial
space of endothelium.
The claims stand rejected as follows:
Claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, 114, 115, and 117
under 35 U.S.C. § 112, first paragraph, as lacking adequate written
description (Ans. 6);
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Claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, 114, 115, and 117
under 35 U.S.C. § 112, first paragraph, as nonenabled (Ans. 2);
Claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, and 78 under 35 U.S.C.
§ 103 (a) as obvious based on Blumberg,2 Presta, 3 Maruyama, 4 and either
Farokhzad5 or Cheng6 (Ans. 9);
Claims 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, and 114 under 35
U.S.C. § I03(a) as obvious based on Blumberg, Presta, Maruyama, either
Farokhzad or Cheng, and Harris 7 (Ans. 12-13);
Claims 1, 115, and 117 under 35 U.S.C. § I03(a) as obvious based on
Blumberg, Presta, Maruyama, either Farokhzad or Cheng, Harris, and
Ruoslahti8 (Ans. 13-14).
I
The Examiner has rejected all of the claims on appeal for lack of
adequate written description and nonenablement. The Examiner relies on
2 Blumberg et al., US 6,060,613, issued Feb. 29, 2000.
3 Presta, US 6,737,056 Bl, issued May 18, 2004.
4 Maruyama et al., Tragetability of novel immunoliposomes modified with
amphipathic poly(ethylene glycol)s conjugated at their distal terminals to
monoclonal antibodies, 1234 BIOCHIMICA ET BIOPHYSICA ACTA 74--80
(1995).
5 Farokhzad et al., Nanoparticle-Aptamer Bioconjugates: A New Approach
for Targeting Prostate Cancer Cells, 64 CANCER RESEARCH 7668-7672
(2004).
6 Cheng et al., Formulation of Functional PLGA-PEG Nanoparticlesfor in
vivo targeted drug delivery, 28 BIOMATERIALS 869-876 (2007).
7 Harris et al., Proteolytic Actuation of Nanoparticle Self-Assembly, 118
ANGEW. CHEM. 3233-3237 (2006).
8 Ruoslahti et al., US 7,488,792 B2, issued Feb. 10, 2009.
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similar fact-finding and reasoning for both rejections. We will therefore
address them together.
Regarding the written description requirement, the Examiner finds
that"[ w ]ith respect to the FcRn binding partner, the only disclosure in the
specification appears to be IgG antibodies having the Fe region." Ans. 6.
Similarly, regarding enablement, the Examiner finds that, "[ w ]ith respect to
the F cRn binding partner comprising IgG F c fragment at least 80%
homologous to SEQ ID NO: 1, the only disclosure in the specification
appears to be antibodies having the full length IgG Fe region." Ans. 3.
With regard to both rejections, the Examiner finds that "there is
insufficient guidance and directions regarding how to modify the Fe region
for an Fe fragment including a fragment that is at least 80% identical to
human IgG Fe region including SEQ ID NO: 1 or how to use whole
antibodies with different antigen specificities while maintaining the
functions, e.g. binding to FcRn." Id. at 3, 6.
The Examiner finds that the prior art shows that "even single amino
acid differences can result in drastically altered binding affinity of the Fe
region of antibodies to FcRn." Id. at 4, citing Martin. 9 The Examiner also
finds that determinants of antibody properties, including solubility and
affinity, are overlapping, so that "engineering an antibody to be more soluble
may cause a loss in affinity for its antigen." Id., citing Lazar. 1° Finally, the
9 Martin et al., Crystal Structure at 2.8 A of an FcRn/Heterodimeric Fe
Complex: Mechanism of pH-Dependent Binding, 7 MOLECULAR CELL 867-
877 (2001).
10 Lazar et al., WO 03/074679 A2, Sept. 12, 2003.
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Examiner finds that "a large number of residues were found that affected
binding ofigGl to human FcRn." Id., citing Shields. 11 The Examiner
repeats these findings in rejecting the claims for lack of adequate descriptive
support. Id. at 8.
The Examiner concludes that it is not clear that the in vitro results
described in the Specification, using the full-length Fe region of human IgG,
"would be sufficient to enable the entire genus" of the claims, id., and that
"the experimentation left to those skilled in the art, is unnecessarily, and
improperly, extensive and undue." Id. at 6. The Examiner also concludes
that "it does not appear based upon the limited disclosure of full length Fe
region of IgG alone and specific agent ( e.g. CREKA) alone that appellant
was in possession of the necessary common attributes or features of the
elements possessed by the members of the genus." Id. at 8-9.
With respect to written description, Appellants argue that "claim 1 is
not drawn to genera of FcRn binding partners lacking any common
structure, as alleged by the Examiner. In contrast, the structural features
required to perform the claimed function of binding to the FcRn are
explicitly defined." Appeal Br. 13. More specifically, "the points of contact
between the component of the Fe portion ofigG that bind to the FcRn
receptor, as determined by X-ray crystallography, are explicitly recited in
the specification (see paragraph [0005] ... )." Id. at 14. Appellants also
argue that "the crystal structure and description of the contacts between the
11 Shields et al., High Resolution Mapping of the Binding Site on Human
IgG 1 for Fey RI, FcyRIL FcyRIIL and FcRn and design of IgG 1 Variants
with Improved binding to the FcyR, 276 J. BIOL. CHEM. 6591-6604 (2001).
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Fe portion of IgG and the FcRn receptor were published in 1994." Id., citing
Burmeister. 12 Appellants conclude that "one of skill in the art would
recognize the Appellants were in possession of the necessary common
attributes or features of the elements possessed by the claimed
nanoparticles." Id. at 20.
With respect to enablement, Appellants argue that "the specification
recognizes that certain positions in the Fe region can be modified and states
that positions remote from the FcRn contact sites as well as modifications
within the FcRn contact sites can be modified to preserve or enhance the Fc-
FcRn interactions, as set forth in paragraph [0005]" of the Specification.
Appeal Br. 27. Appellants also argue that "methods to modify proteins and
peptides through addition, deletion, mutation or otherwise altering one or
more amino acids within a protein were routine" in the art as of this
application's filing date. Id. Appellants conclude that a person of ordinary
skill in the art could make and use the claimed nanoparticles "based on the
guidance set forth in the specification as filed, and the level of ordinary skill
in the art at the time of filing." Id. at 31.
We agree with Appellants that, based on the Specification's disclosure
and the knowledge existing in the art at the time this application was filed, a
person of ordinary skill in the art would not have needed to carry out undue
experimentation to practice the claimed invention and would have
recognized that Appellants were in possession of the claimed invention
based on the Specification's description of it.
12 Burmeister et al., Crystal structure of the complex of rat neonatal Fe
receptor with Fe, 372 NATURE 379--383 (1994).
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"Whether undue experimentation is needed is not a single, simple
factual determination, but rather is a conclusion reached by weighing many
factual considerations." In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
Among those considerations are the state of the prior art, the relative skill of
those in the art, and the predictability or unpredictability of the art. Id. "The
specification need not explicitly teach those in the art to make and use the
invention; the requirement is satisfied if, given what they already know, the
specification teaches those in the art enough that they can make and use the
invention without 'undue experimentation."' Amgen, Inc. v. Hoechst
Marion Roussel, Inc., 314 F.3d 1313, 1334 (Fed. Cir. 2003).
A "sufficient description of a genus ... requires the disclosure of
either a representative number of species falling within the scope of the
genus or structural features common to the members of the genus so that one
of skill in the art can 'visualize or recognize' the members of the genus."
Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010)
(en bane). However, "[t]he 'written description' requirement must be
applied in the context of the particular invention and the state of the
knowledge." Capon v. Eshhar, 418 F.3d 1349, 1358 (Fed. Cir. 2005).
"[T]he determination of what is needed to support generic claims to
biological subject matter depends on a variety of factors, such as the existing
knowledge in the particular field, the extent and content of the prior art, the
maturity of the science or technology, the predictability of the aspect at
issue, and other considerations appropriate to the subject matter." Id. at
1359.
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Here, the evidence of record shows that the relevant amino acid
residues in the Fe fragment of IgG were well-known at the time the instant
application was filed. The Specification states that
[t]he region of the Fe portion of IgG that binds to the FcRn
receptor has been described based upon X-ray crystallography
(Burmeister, et al., 1994, Nature, 372:379; incorporated herein
by reference). The major contact area of Fe with the FcRn
receptor is near the junction of the CH2 and CH3 domains.
Potential contacts are residues 248, 250-257, 272, 285, 288,
290-291, 308-311, and/or 314 in CH2 and 385-387, 428, and/or
433-436 in CH3.
Spec. ,r 5. The Specification's statements are supported by Burmeister. See
Burmeister 379, right col. and 383, Table 2(a).
In addition, the Martin and Shields references cited by the Examiner
show that numerous amino acid changes in the Fe domain of IgG had
previously been made, and disclose the effect of those changes on Fc/FcRn
interactions. Martin, for example, discloses mutations in the human IgG 1 Fe
domain that either reduced or enhanced binding to human FcRn. Martin
874, Table 4. "From these results and an analysis of the FcRn/hdFc
[heterodimeric version of F c] structure, [Martin] suggest[ s] a general
strategy for identification of Fe mutants with increased affinity for FcRn."
Id. at 873-874.
Shields discloses "a complete, high resolution mapping of human
IgG 1 ... for human FcRn." Shields 6592, left col. "The binding site on
human IgG 1 for the various receptors was determined by individually
changing all solvent-exposed amino acids in human IgG 1 CH2 and CH3
domains ... to Ala." Id. Shields discloses the "[b ]inding of human IgG 1
variants to human FcRn." Id. at 6595, Table I. Among the variants are
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those in Class 10, which "affect only FcRn." Id. Some of the Class 10
variants showed reduced binding and some showed improved binding,
compared to native IgG 1. Id.; see also id. at footnote b.
The Examiner also cites Lazar's disclosure that "the determinants of
antibody stability, solubility, and affinity for antigen are overlapping and the
interactions that contribute to these properties are related. Thus, affinity
maturation of an antibody may result in decreased stability, and optimization
of an antibody's solubility may cause a loss in affinity for its antigen."
Lazar 3:21-24; see also Ans. 4, 8. However, this teaching is of limited
relevance to the claimed invention, which is based on the interaction of the
Fe domain ofigGl with the FcRn receptor, not on the antigenic specificity
of any given antibody.
Thus, the evidence shows that those skilled in the art were aware of
what portions of the Fe domain were responsible for FcRn interaction (Spec.
,r 5, Burmeister), and were aware of the effects of various amino acid
substitutions on the Fc/FcRn interaction (Martin, Shields). The evidence
also shows that Martin had suggested, before the instant application's filing
date, "a general strategy for identification of Fe mutants with increased
affinity for FcRn." Martin 873-74.
In view of the existing knowledge in the art, the high level of skill in
the art, and the routine nature of making and testing substitution mutations in
the IgG Fe domain, as evidenced by Martin and Shields, we conclude that
the Examiner has not shown by a preponderance of the evidence that undue
experimentation would be required to make and use the claimed
nanoparticles. Similarly, in view of the "the existing knowledge in the
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particular field, the extent and content of the prior art, [and] the maturity of
the science or technology" Capon, 418 F.3d at 1359, the Examiner has not
shown by a preponderance of the evidence that those skilled in the art would
not have recognized from the Specification's description that Appellants
were in possession of the claimed genus of nanoparticles.
In summary, we reverse both of the rejections under 35 U.S.C. § 112,
first paragraph.
II
The Examiner has rejected claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76,
and 78 under 35 U.S.C. § 103(a) as obvious based on Blumberg, Presta,
Maruyama, and either Farokhzad or Cheng. The Examiner finds that
Blumberg discloses "delivery of a therapeutic drug or an antigen by
administering to the luminal side of an epithelial barrier of an epithelial
tissue expressing an FcRn receptor a conjugate of an FcR[n] binding partner
and a drug or antigen." Ans. 9. The "binding partner can be Fe fragment of
the human IgG." Id. "[T]he FcRn mediated transport system can be used
for the delivery of a wide variety of compounds including chemotherapeutic
agent[s]." Id. at 10.
The Examiner finds that Presta discloses the amino acid sequence of
the human IgG 1 Fe region. Id. The Examiner cites Appellants'
Specification as evidence that the amino acid sequence of SEQ ID NO: 1,
recited in claim 1, is from human IgG 1. Id.
The Examiner finds that Maruyama discloses liposomes modified
with polyethylene glycol (PEG) molecules having antibodies attached at
their distal termini. Id. The Examiner also finds that Maruyama suggests
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using the resulting immunoliposomes for targeted drug delivery because
they should provide high local concentrations of an encapsulated drug at a
target site. Id. at 10-11.
The Examiner finds that both Farokhzad and Cheng teach polymeric
nanoparticles, which included PEG as part of the polymer, conjugated to
aptamers. Id. at 11-12. The Examiner finds that Farokhzad suggests using
the nanoparticle conjugates for targeted delivery of chemotherapeutic drugs
and Cheng suggests using conjugates that include an aptamer that binds to
prostate specific membrane antigen (PMSA) for targeted tumor-specific
drug delivery. Id.
The Examiner concludes that it would have been obvious to use the
IgG 1 Fe delivery system taught by Blumberg to deliver the nanoparticles of
Farokhzad or Cheng with the antibody attached to their surface via PEG, as
taught by Maruyama, to deliver chemotherapeutic agents, as suggested by
both Farokhzad or Cheng. Id. at 12.
We agree with the Examiner that the nanoparticles of claim 1 would
have been obvious to a person of ordinary skill in the art based on the cited
references. Blumberg discloses that "antigens may be coupled to molecules
that bind to the FcRn receptor, such as immunoglobulins, or portions
thereof, and delivered across epithelial barriers ... via FcRn receptors."
Blumberg 3 :36-40. The most preferred FcRn binding partner is an Fe
fragment of IgG. Id. at 4:2--4. "[T]he FcRn binding partner may be
produced by recombinant genetic engineering techniques. Within the scope
of the invention are nucleotide sequences encoding human FcRn binding
partners." Id. at 6:65 to 7:2.
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Blumberg states that "[t]he FcRn receptor binds IgG (but not other
immunoglobulin classes such as IgA, IgD, IgM and IgE) at a relatively
lower pH, actively transports the IgG transcellularly in a luminal to serosal
direction, and then releases the IgG at a relatively higher pH found in the
interstitial fluids." Id. at 6:31-36. Blumberg states that its conjugates are
therefore "useful whenever it is desirable to achieve systemic delivery of a
therapeutic or drug or delivery vehicle across an epithelial barrier to
systemic circulation," and "may be used to deliver therapeutics across
intestinal epithelial tissue, lung epithelial tissue, and other mucosal epithelial
surfaces." Id. at 5:43--48.
Blumberg also teaches that "FcRn binding partners ... may be
utilized for the delivery of a wide variety of compounds and therapeutics and
bioactive substances, including but not limited to, chemotherapy agents for
the treatment of cancer," etc. Id. at 3 :58---61. Blumberg teaches that its
conjugates can include "a variety of therapeutics or drugs for targeted
systemic delivery." Id. at 11:66---67; see also id. at 12:22 to 13:62 (listing
exemplary drugs that can be used). "The FcRn binding partners of the
present invention may further be utilized for the targeted delivery of a
delivery vehicle, such as liposomes." Id. at 3:64---67.
Presta discloses the amino acid sequence of the human IgG 1 F c
region. Presta 9:18-20 and Fig. 22A. Appellants' Specification provides
evidence that SEQ ID NO: 1, recited in claim 1, is "the sequence of the Fe
portion of a human IgG 1 antibody." Spec. ,r 54.
Maruyama discloses that DSPE-PEG-COOH (distearoyl-N-(3-
carboxypropionoyl poly( ethylene glycol) succinyl)phosphatidylethanolamine)
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was "used to prepare novel immunoliposomes carrying monoclonal antibodies
at the distal ends of the PEG chains (Type C)." Maruyama 74, abstract.
Maruyama's Figure 1 is reproduced below:
Type A Type a Type C
Figure 1 shows "immobilization of antibody on liposomes. . . . Type C: new
type of PEG-immunoliposomes with antibody attached to the distal terminal
of DSPE-PEG-COOH." Id. at 75, legend to Figure 1. Maruyama states that
"conjugation of antibody directly to the PEG terminal provides excellent
target binding and retention of immunoliposomes." Id. at 80, left col.
Maruyama also states that "Type C liposomes have great potential as a
targeted drug delivery vehicle. They should be able to provide a high local
concentration of the encapsulated drug at the target site for a prolonged period
of time." Id.
Farokhzad discloses nanoparticles "synthesized [from] poly(lactic
acid)-block-polyethylene glycol (PEG) copolymer with a terminal carboxylic
acid functional group (PLA-PEG-COOH)." Farokhzad 7668, abstract. The
nanoparticles have "carboxylic acid groups on the particle surface for
potential modification and covalent conjugation to amine-modified aptamers."
Id. Farokhzad "generated nanoparticle-aptamer bioconjugates with RNA
aptamers that bind to the prostate-specific membrane antigen, a well-known
prostate cancer tumor marker." Id. The PLA-PEG-COOH nanoparticles had
a mean size of 249 ± 12 nm. Id. at 7669, Fig. 1. Farokhzad states that its
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"nanoparticle-aptamer bioconjugates, which target and are taken up by
prostate cancer epithelial cells[,] ... are potentially suitable for efficient and
specific targeted delivery of chemotherapeutic drugs to prostate cancer cells."
Id. at 7671, left col.
Cheng also discloses polymeric nanoparticles (NPs) conjugated to an
aptamer (Al 0) that targets prostate-specific membrane antigen (PMSA), but
its nanoparticles were made from a different polymer (PLGA-b-PEG-COOH)
than Farokhzad's nanoparticles. Cheng 869, abstract. "The surface
functionalization ofNPs with the AIO PSMA Apt significantly enhanced
delivery ofNPs to tumors." Id. "Cheng states that its nanoparticles provide
"tumor specific systemic targeting of a NP-Apt bioconjugate system in vivo
and may result in the development of therapeutically effective vehicles for
disseminated prostate cancer." Id. at 875, left col.
Based on the cited references, the nanoparticles of claim 1 would have
been obvious to a person of ordinary skill in the art. Blumberg teaches that a
therapeutic agent that is conjugated to an FcRn binding partner, such as an Fe
fragment of human IgG, will be transported from the surface of epithelial
tissue into the interstitial fluid and into the systemic circulation. Presta
teaches the FcRn binding region of human IgGl (SEQ ID NO: 1). Thus, it
would have been obvious to use the FcRn binding region of the Fe fragment
of human IgG 1 as the FcRn binding partner in Blumberg's conjugates with a
therapeutic agent.
Although Blumberg does not disclose using its conjugates to deliver
nanoparticles containing a therapeutic agent, it does disclose that F cRn
binding partners can be used for targeted delivery to the systemic circulation
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of delivery vehicles, such as liposomes. Both Farokhzad and Cheng disclose
that polymeric nanoparticles having PEG moieties on the surface can be
conjugated to a binding partner, such as an RNA aptamer, in order to deliver a
drug to particular cells. Thus, it would have been obvious to modify
Blumberg's FcRn-targeted liposomes by substituting the polymeric
nanoparticles taught by Farokhzad and Cheng for Blumberg's liposomes. See
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007) ("[W]hen a patent
claims a structure already known in the prior art that is altered by the mere
substitution of one element for another known in the field, the combination
must do more than yield a predictable result." (discussing United States v.
Adams, 383 U.S. 39, 50-51 (1966))).
Both Farokhzad and Cheng disclose that target-specific aptamers are
conjugated to the polymeric nanoparticles via PEG moieties on the surface of
the nanoparticles. Maruyama similarly teaches that antibodies can be
conjugated to PEG moieties on the surface of liposomes in order to target a
drug to a target site. Based on these teachings, it would have been obvious to
attach the FcRn-binding IgG 1 Fe fragment suggested by Blumberg and Presta
to the PEG moieties on the surface of the polymeric nanoparticles of
Farokhzad or Cheng, in order to target the nanoparticles to the FcRn receptor,
as taught by Blumberg.
In summary, the cited references disclose all of the limitations of claim
1 and provide a reason to combine the elements of the claimed nanoparticles
in the manner recited in the claim. Claim 1 therefore would have been prima
facie obvious to a person of ordinary skill in the art, based on the cited
references.
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Appellants argue that "Cheng represents the inventor's own work and
is not available as effective prior art to the claimed subject matter." Appeal
Br. 39, citing the Farokhzad Declaration. 13
We conclude that the Farokhzad Declaration is sufficient to show that
Cheng does not represent a disclosure "by others," 35 U.S.C. § 102(a), and
therefore does not qualify as prior art with respect to the claimed invention.
The Examiner concludes that "[t]he Farokhzad declaration is insufficient to
demonstrate that Cheng et al. is appellants' own work," Ans. 25, but cites no
evidence that contradicts the declaration's statement that the authors of
Cheng who are not inventors of the instant application "did not contribute to
the conception or reduction to practice of the [ claimed] functionalized
nanoparticles for targeted drug delivery." Farokhzad Deel. ,r 3.
"[ A ]uthorship of an article by itself does not raise a presumption of
inventorship with respect to the subject matter disclosed in the article. Thus,
co-authors may not be presumed to be coinventors merely from the fact of
co-authorship." In re Katz, 687 F.2d 450, 455 (CCPA 1982). Here, the
inventors have declared that the authors of Cheng who are not named as
inventors of the instant application did not make an inventive contribution to
the claimed products. Given the absence of evidence to the contrary, we
13 Declaration of all of the inventors, filed June 30, 2015. Although the
Declaration states that it was filed under 3 7 C.F .R. § 1.131, the purpose of
the declaration is to show that the non-inventor authors of Cheng "did not
contribute to the conception or reduction to practice of the [ claimed]
functionalized nanoparticles for targeted drug delivery." Farokhzad Deel.
,r 3. We therefore have treated the declaration as having been filed under 37
C.F.R. § 1.132. See In re Katz, 687 F.2d450 (CCPA 1982).
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accept the declaration's statement as accurate. Therefore, Cheng does not
qualify as prior art with respect to the claims on appeal.
We conclude that the remaining references support a prima facie case
of obviousness, however, because the relevant teachings of Cheng are also
provided by Farokhzad. Thus, Blumberg, Presta, Maruyama, and Farokhzad
support a prima facie case of obviousness with respect to claim 1.
Appellants also argue that none of Blumberg, Presta or Maruyama
disclose or suggest nanoparticles, and Farokhzad does not disclose FcRn
binding partners. Appeal Br. 41--43. "Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references." In re Merck & Co., 800
F.2d 1091, 1097 (Fed. Cir. 1986). "The test for obviousness is what the
combined teachings of the references would have suggested to one of
ordinary skill in the art." In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991).
Here, for the reasons discussed above, we conclude that the combined
teachings of Blumberg, Presta, Maruyama, and Farokhzad would have made
obvious the nanoparticles defined by claim 1.
Appellants argue that "none of the cited art could lead the skilled
person to combine Presta, Farokhzad or Maruyama with Blumberg, because
none of these references suggest that polymeric nanoparticles including
active agents can exploit surface-bound Fe to initiate FcRn-mediated
transcytosis of a nanoparticle of greater than 10 nm in size." Appeal Br. 46.
Appellants argue that "[i]t was not known prior to Appellant's filing date
that polymeric nanoparticles (i.e., 10-500 nm in size) could exploit the
FcRn-mediated trans-cellular pathway mechanism to achieve the targeted
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delivery of therapeutic, diagnostic or prognostic agents to the interstitial
space." Id. at 43. Appellants argue that "[t]he use of an Fc/FcRn interaction
to mediate internalization and transcytosis of a nanoparticle delivery vehicle
represents an unexpected and surprising result in view of the cited art, at
least because of the unique pH-dependence of the FcRn interactions." Id.
These arguments are unpersuasive. Farokhzad states that its
"nanoparticle-aptamer bioconjugates ... are taken up by prostate cancer
epithelial cells." Farokhzad 7 671, left col. ( emphasis added). A person of
ordinary skill in the art would therefore expect that nanoparticles 249 nm in
size (like those ofFarokhzad) would be taken up by-i.e., internalized or
endocytosed-by target cells to which they bind. Appellants have pointed to
no evidence showing that cells expressing the F cRn receptor differ in their
endocytosis characteristics from the prostate cancer epithelial tissues
targeted by Farokhzad's bioconjugates.
In addition, the pH-dependence of FcRn/IgG interactions was well
known in the art. See Blumberg 2:9-20 ("[T]he Fe portion of IgG is bound
to the enterocyte receptor at the relatively acidic pH of the lumen ( about pH
6.0). Following transcytosis to the basolateral plasma membrane, discharge
of the immunoglobulin occurs at the relatively neutral pH of the interstitial
fluids (about pH 7.4).").
Thus, the cited references support the Examiner's conclusion that a
person of ordinary skill in the art would have had a reason to combine their
respective teachings with a reasonable expectation of success. The evidence
does not support Appellants' argument that the claimed nanoparticles
provide surprising or unexpected results.
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Appellants argue that "nothing in the cited art teaches or suggests the
specific interaction of the claimed nanoparticles with endothelial or
epithelial cells defined by claim 15." Appeal Br. 47--48. However,
Blumberg expressly states that its conjugates can be used "to achieve
systemic delivery of a therapeutic or drug or delivery vehicle across an
epithelial barrier to systemic circulation," and "may be used to deliver
therapeutics across intestinal epithelial tissue, lung epithelial tissue, and
other mucosal epithelial surfaces." Blumberg 5:43--48. The cited references
therefore would have made obvious nanoparticles that are able to bind to the
F cRn receptor of epithelial cells, as recited in claim 15.
With respect to claims 36, 39, 75, 76, and 78, Appellants argue that,
"[a]s discussed, nothing in the combination of art describes or suggests
polymeric nanoparticles including surface-bound FcRn binding partners,
irrespective of the type of association between the particle and the FcRn
binding partner, and/or therapeutic, diagnostic, prognostic, or prophylactic
agent." Appeal Br. 48. This argument is unpersuasive for the reasons
discussed above.
With respect to claims 20 and 27, Appellants argue that, "nothing in
the combination of the cited art teaches or suggests polymeric nanoparticles
including FcRn binding partners can be useful for the delivery of
therapeutics to interstitial spaces through FcRn-mediated transcytosis across
an endothelial cell layer." Appeal Br. 49.
This argument is unpersuasive. Blumberg discloses that its conjugates
can be used to deliver a variety of drugs to the systemic circulation by oral
or pulmonary administration (i.e., inhalation), as recited in claim 27. See
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Blumberg 16:53-56. Blumberg also discloses that its conjugates can be
used to deliver, among other things, a thrombolytic agent (tissue
plasminogen activator), as recited in claim 20. Id. at 13:30-31. Thus, the
cited references would have made obvious the nanoparticles of claims 20
and 27.
With regard to claim 32, Appellants argue that "no art has been cited
to lead one skilled in the art to believe liposomes are equivalent in structure
or function, or can be targeted in the same way." Appeal Br. 49-50.
Claim 32 recites specific polymers for the claimed polymeric
nanoparticles, including polylactic acid and polyethylene glycol. Farokhzad
discloses nanoparticles made from poly(lactic acid)-block-polyethylene
glycol copolymer. Farokhzad 7668, abstract. For the reasons discussed
above, therefore, the cited references therefore would have made obvious the
nanoparticles defined by claim 32.
With respect to claim 38, Appellants argue that Blumberg "is drawn to
a single Fe or IgG conjugated to antigen. Nothing in the combination of
Blumberg and the other cited art references teaches or suggests polymeric
particles, least of all nanoparticles having a multiplicity of FcRn binding
partners associated with their surface." Appeal Br. 50.
This argument is unpersuasive. For the reasons discussed above, the
cited references would have made obvious the combination of Blumberg' s
FcRn binding partners and Farokhzad's polymeric nanoparticles and, given
their relative sizes, a skilled artisan would have reasonably expected that the
nanoparticles would have multiple FcRn binding partners associated with
their surfaces. In addition, Farokhzad discloses that its nanoparticles have
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carboxylic acid "groups" (plural) on their surfaces for conjugation to
"aptamers" (plural). Farokhzad 7668, abstract. Thus, the cited references
would have made obvious the nanoparticles defined by claim 38.
IV
The Examiner has rejected claims 15, 20, 27, 32, 36, 38, 39, 75, 76,
78, 112, and 114 as obvious based on Blumberg, Presta, Maruyama, either
Farokhzad or Cheng, and Harris.
With regard to claims 112 and 114, Appellants argue that "Harris does
not make up for the deficiencies of Blumberg, Presta, Farokhzad, Maruyama
and Cheng, at least because Harris does not teach or suggest polymeric
nanoparticles, or FcRn binding partners having at least 80% homology to
SEQ ID NO.: 1, least of all nanoparticles having a multiplicity of such
molecules at the surface of the particle." Appeal Br. 51. Appellants also
argue that "[ n ]othing in Harris could lead one skilled in the art to recognize
that FcRn-mediated transcytosis could be useful to transport nanoparticles
including therapeutic, diagnostic or prognostic agents across the endothelial
cell layer." Id. at 51-52.
This argument is not persuasive because, for the reasons discussed
previously, we conclude that Blumberg, Presta, Maruyama, and Farokhzad
would have made obvious polymeric nanoparticles with multiple FcRn
binding partners having at least 80% homology to SEQ ID NO: 1 on their
surfaces, as well as FcRn-mediated transcytosis of nanoparticles that include
a therapeutic agent across an endothelial cell layer. Therefore, we do not
find any deficiency in the teachings of Blumberg, Presta, Maruyama, and
Farokhzad with respect to the argued claim limitations.
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With regard to claims 15, 20, 27, 32, 36, 38, 39, 75, 76, and 78,
Appellants argue that "at least for the reasons described above with respect
to claims 112 and claims 114, Harris does not make up for the deficiencies
of Blumberg, Presta, Farokhzad, Maruyama and Cheng." Appeal Br. 52.
This argument is unpersuasive for the reasons discussed above. We
therefore affirm the rejection of claims 15, 20, 27, 32, 36, 38, 39, 75, 76, 78,
112, and 114 under 35 U.S.C. § 103(a) based on Blumberg, Presta,
Maruyama, Farokhzad, and Harris.
V
The Examiner has rejected claims 1, 115, and 117 under 35 U.S.C.
§ 103(a) as obvious based on Blumberg, Presta, Maruyama, either
Farokhzad or Cheng, Harris, and Ruoslahti.
With respect to claim 1, Appellants argue that "Ruoslahti does not
make up for the deficiencies of Blumberg, Presta, Farokhzad, Maruyama,
Harris and Cheng." Appeal Br. 53. For the reasons discussed above,
however, we conclude that the nanoparticles of claim 1 would have been
obvious based on the disclosures of Blumberg, Presta, Maruyama, and
Farokhzad. We therefore do not find any deficiency in their disclosures that
requires remedy by Harris.
With respect to claim 115, 14 the Examiner finds that a "peptide
comprising the sequence of CREKA selectively homes to tumor vascular"
14 Claim 115 is directed to "[t]he nanoparticle of claim 1, further comprising
a targeting moiety on surface of the nanoparticle, wherein the targeting
moiety is a peptide comprising CREKA (SEQ ID N0.:7) amino acid
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and "can be linked to polymeric matrix," and that "the homing properties of
the CREKA to the tumor site would reduce the side effect associated with
systemic delivery." Ans. 14. The Examiner concludes that it would have
been obvious "to add CREKA peptide to the nanooparticle' s [sic] surface in
order to target tumor vascular." Id.
We agree with, and adopt, the Examiner's fact-finding and
conclusion.
Appellants argue that "Ruoslahti states that the five amino acid
sequence CREKA ... interacts with all forms of collagen" and therefore
"Ruoslahti does not teach or suggest a ligand that specifically binds collagen
in the extracellular matrix of the basal lamina, as claimed." Appeal Br. 54--
55.
This argument is not persuasive, because claim 115 requires only that
the nanoparticles comprise a CREKA-containing peptide as a targeting
moiety, and that the peptide "binds to collagen IV." Claim 115 does not
require the targeting moiety to bind "specifically" to collagen IV or exclude
binding to other types of collagens. We therefore agree with the Examiner
that the nanoparticles defined by claim 115 would have been obvious based
on Blumberg, Presta, Maruyama, Farokhzad, Harris, and Ruoslahti.
Claims 11 7 was not argued separately and therefore falls with claim
115. 37 C.F.R. § 4I.37(c)(l)(iv).
sequence which binds to collagen IV and components thereof present in the
extracellular matrix of the basal lamina."
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SUMMARY
We reverse the rejections under 35 U.S.C. § 112, first paragraph, for
lack of enablement and lack of adequate written description.
We affirm all of the rejections under 35 U.S.C. § 103(a).
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
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