Ex Parte VLAHOV et al

Patent Trial and Appeal Board

Feb 4, 2019

13740784 (P.T.A.B. Feb. 4, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/740,784 01/14/2013 Iontcho R. VLAHOV
23643 7590 02/06/2019
Barnes & Thornburg LLP (IN)
11 S. Meridian Street
Indianapolis, IN 46204
UNITED ST A TES OF AMERICA
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.
20150-223823 5231
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
02/06/2019 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):
INDocket@btlaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte IONTCHO R. VLAHOV and
CHRISTOPHERP. LEAMON 1
Appeal2017---003868
Application 13/740,784
Technology Center 1600
Before TONI R. SCHEINER, DEMETRA J. MILLS, and
JOHN G. NEW, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants identify Endocyte, Inc. as the real party-in-interest. App. Br. 3.
Appeal2017---003868
Application 13/740,784
SUMMARY
Appellants file this appeal under 35 U.S.C. § I34(a) from the
Examiner's Final Rejection of claims 1 and 53-70. Specifically, claim 1
stands rejected as unpatentable under 35 U.S.C. § 112, second paragraph, as
being indefinite.
Claim 1 also stands rejected as unpatentable under 35 U.S.C. § I03(a)
as being obvious over Vlahov et al. (WO 2004/069159 A2, August 19, 2004)
("Vlahov"), and Russell-Jones et al. (WO 00/66091, November 9, 2000)
("Russell-I ones").
Claims 1 and 53-70 stand rejected as unpatentable under 35 U.S.C.
§ I03(a) as being obvious over Vlahov, Russell-Jones, and Matulic-Adamic
et al. (US 2005/0239739 Al, October 27, 2005) ("Matulic-Adamic"). 2
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to compounds, pharmaceutical
compositions, and methods for treating pathogenic cell populations in a
patient, including conjugates of a plurality of cytotoxic drugs and vitamin
receptor binding ligands. Abstr.
2 Claims 1 and 53-70 also stand rejected on the ground of non-statutory
obviousness-type double patenting as being unpatentable over claims 1-14
of US 8,105,568 (January 31, 2012), Russell-Jones, Matulic-Adamic, and
Vlahov. See Final Act. 8. Appellants do not address this rejection and we
consequently summarily affirm the rejection. See 37 C.F.R. § 41.37 (c)(iv)
("[ A ]ny arguments or authorities not included in the appeal brief will be
refused consideration by the Board for purposes of the present appeal").
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REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A receptor binding drug delivery conjugate
compnsmg:
(a) a receptor binding moiety;
(b) a polyvalent linker; and
( c) two or more drugs, or analogs or derivatives thereof;
wherein the receptor binding moiety is covalently linked to the
polyvalent linker;
the two or more drugs, or analogs or derivatives thereof, are
covalently linked to the polyvalent linker;
the polyvalent linker comprises one or more fragments selected
from the group consisting of
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and
wherein
CO,.J-1
'-,·~- __ ,....J,_ ..,....,/,."""' __ ,,...-
-~ /y-\ s
\ '
Ra and Rb are each independently selected from the group
consisting of hydrogen and Cl--C4 alkyl, or Ra and Rb are taken
together with the attached carbon atom to form a carbocyclic
rmg;
R is an optionally substituted alkyl group or an optionally
substituted acyl group;
n is an integer from 1 to 4; and
mis an integer from 1 to 4;
or a pharmaceutically acceptable salt thereof.
App. Br. 16-18.
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Application 13/740,784
ISSUES AND ANALYSES
We are not persuaded by the Examiner's findings and conclusion that
the scope of claim 1 is indefinite. We agree with, and adopt, the Examiner's
findings and conclusion that claims 1 and 53-70 are primafacie obvious
over the combined cited prior art. We address Appellants' dispositive
argument below.
A. Rejection of claim 1 under 35 U.S.C. § 112, second paragraph
Issue
Appellants argue that the Examiner erred in concluding that the claim
terms "receptor binding moiety" and "drug" are ambiguous and therefore
indefinite. App. Br. 8.
Analysis
The Examiner finds that sections of Appellants' Specification relied
upon by Appellants as defining the claim terms at issue merely provide
examples, which do not define the meets and bounds of the terms. Final
Act. 3 (see Spec. 5---6, 12-14). The Examiner finds the claim term "drug" is
generally understood to mean a substance that has a physiological effect
when administered to the body. Id. The Examiner therefore finds that the
folate targeting agent of Vlahov reads as both a receptor-binding moiety and
a drug. Id. The Examiner finds that, using this interpretation, the conjugates
of Vlahov read on conjugates of at least two drugs in which one drug is that
folate targeting agent and the other drug is the therapeutic agent. Id.
Appellants argue that their Specification provides clear and detailed
description regarding what is encompassed by the claim term "receptor
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Application 13/740,784
binding moiety." App. Br. 8 (citing Spec. 5-6, 12-14). Appellants contend
that the Specification equates the term "receptor binding moiety" with a
"ligand." Id. (citing, e.g., Spec. 2, 12-13). According to Appellants, the
term "ligand" is a well understood, widely used, term in the field of
biochemistry. Id. Appellants assert that the Specification makes clear that
the phrase "receptor binding moiety" refers to a ligand of a cell surface
receptor. Id. (citing, e.g., 5, 12). Therefore, Appellants argue, a person of
ordinary skill in the art would have understood that a "receptor binding
moiety," as recited in claim 1, refers to a ligand configured for binding to a
complementary receptor (e.g., of a pathogenic cell).
By way of example, Appellants point to page 7, lines 3---6 of the
Specification as disclosing: "members of the pathogenic cell population have
an accessible binding site for a receptor binding moiety, or the analog or
derivative thereof, and that binding site is uniquely expressed,
overexpressed, or preferentially expressed by the pathogenic cells." App.
Br. 8-9.
Appellants argue that, given such a description, and the numerous
examples of representative "receptor binding moieties" disclosed by the
Specification, and further given the well-established meaning of the term
"ligands" in the field of biochemistry, a person of ordinary skill in the art
would have understood the meaning of the phrase "receptor binding
moiety," as recited in claim 1. App. Br. 9.
With respect to the claim term "drug," Appellants point to page 6 of
their Specification, which discloses: "The drugs, and various analogs and
derivatives thereof, described herein are generally drugs for eliminating,
killing, interfering with, and/or decreasing the growth of a population of
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pathogenic cells, including infectious agents, cancers, tumors, and the like."
App. Br. 9. Appellants contend that, in light of this definition, and in further
view of other examples of representative drugs provided in the specification,
a person of ordinary skill in the art would have understood the meaning of
the claim term "drug" as recited in independent claim 1.
The Examiner responds that the use of the claim terms "receptor
binding moiety" and "drug" together in claim 1 renders the claim indefinite
because the terms are generally understood to be synonymous in meaning.
Ans. 13. However, the Examiner finds the construction of the claim
suggests that the terms should be interpreted differently, because different
terms are used to describe what is generally understood to be the same thing.
Id. The Examiner notes that the Specification's definition of the term
"drug," cited by Appellants, is modified by the word "generally" and finds
that "generally" can be understood as meaning in most cases, rather than in
all cases. Id. Consequently, the Examiner concludes that the terms are
ambiguous when used together because they are open to more than one
interpretation, and it is not clear which species are covered by the terms. Id.
Specifically, the Examiner concludes, it is not clear whether a folate receptor
binding moiety should also be interpreted as a drug. Id.
Appellants reply that "receptor binding moiety" is distinguishable
from "drug," because the Specification reserves "receptor binding moiety"
for a ligand of a cell surface receptor, whereas "drug" is reserved for
compounds configured to impart a desired therapeutic effect vis-a-vis a
population of pathogenic cells. Reply Br. 2. Appellants contend that,
although ligands may be "capable of high affinity binding to receptors on
cancer cells or other types of pathogenic cells," the binding of a ligand to a
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receptor does not necessarily imply that the ligand has a capacity "for
eliminating, killing, interfering with, and/or decreasing the growth of a
population of pathogenic cells," as disclosed by the Specification. Id.
We are persuaded by Appellants' arguments. Appellants'
Specification discloses that:
Ligand conjugates of drugs, and analogs and derivatives
thereof, are described herein. The conjugates include cell
receptor binding ligands that are covalently attached to two or
more drugs that may be targeted to cells. The conjugates
described herein may also include a polyvalent linker for
attaching the ligands to the drugs.
Spec. 2. The Specification further discloses that:
The ligands described herein generally include ligands of
cell surface receptors. Illustrative ligands useful in the conjugates
described herein include, but are not limited to, vitamins, and
other moieties that bind to a vitamin receptor, transporter, or
other surface-presented protein that specifically binds vitamins,
or analogs or derivatives thereof, peptide ligands identified from
library screens, tumor cell-specific peptides, tumor cell-specific
aptamers, tumor cell-specific carbohydrates, tumor cell-specific
monoclonal or polyclonal antibodies, Fab or scFv (i.e., a single
chain variable region), fragments of antibodies such as, for
example, an Fab fragment of an antibody directed to EphA2 or
other proteins specifically expressed or uniquely accessible on
metastatic cancer cells, small organic molecules derived from
combinatorial libraries, growth factors, ligands, cholecystokinin
A receptor ligands, ligands specific for angiotensin ATI or
AT2 receptors, peroxisome proliferator-activated receptor A
ligands, B lactam antibiotics such as penicillin, small organic
molecules including antimicrobial drugs, and other molecules
that bind specifically to a receptor preferentially expressed on
the surface of tumor cells or on an infectious organism,
antimicrobial and other drugs designed to fit into the binding
pocket of a particular receptor based on the crystal structure of
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the receptor or other cell swface protein, ligands of tumor
antigens or other molecules preferentially expressed on the
surface of tumor cells, or fragments of any of these molecules.
Spec. 5---6 ( emphasis added). All of these exemplary compounds are defined
by having the same function, i.e., they are capable of binding to cell surface
receptors. However, and contrary to the Examiner's findings, not all of
these exemplary ligands act as drugs, e.g., tumor cell-specific peptides,
tumor cell-specific aptamers, tumor cell-specific carbohydrates, tumor cell-
specific monoclonal or polyclonal antibodies, Fab or scFv (i.e., a single
chain variable region), fragments of antibodies, or other proteins specifically
expressed or uniquely accessible on metastatic cancer cells. Id.
It is evident from this list of exemplary receptor-binding moieties that
what is meant by the claim term "receptor" is an expressed cell surface or
cytoplasmic (in the case of steroids) protein that is capable of binding the
receptor-binding moiety, and not necessarily a receptor for a drug, as the
Examiner implies. Although some of the listed compounds may also have
effects on the cell's metabolism, all have in common the same basic
functional feature; an ability to bind to a protein expressed on a cell surface
that can act as a receptor for the ligand, and that is how we interpret the
claim term "receptor binding moiety."
With respect to the claim term "drugs," the Specification further
discloses that:
The drugs, and various analogs and derivatives thereof,
described herein are generally drugs for eliminating, killing,
interfering with, and/or decreasing the growth of a population of
pathogenic cells, including infectious agents, cancers, tumors,
and the like. Further, the drugs, and the various analogs and
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derivatives thereof, useful in the conjugates described herein
may have a wide variety of mechanisms of action, including but
not limited to alkylating agents, microtubule inhibitors, including
those that stabilize and/or destabilize microtubule formation,
including beta-tubulin agents, cyclin dependent kinase (CDK)
inhibitors such as CDKNl a. CDKNl b, and the like,
topoisomerase inhibitors, protein synthesis inhibitors, protein
kinase inhibitors, including Ras, Raf, PKC, P13K, and like
inhibitors, transcription inhibitors, antifolates, heat shock protein
blockers, and the like.
Spec. 6. We do not agree with the Examiner that "receptor binding
moieties" and "drugs" are ambiguous terms, because each is defined by the
functional role that they play in the claimed composition: ligands bind to cell
receptors and are also bound to the polyvalent linker, whereas two or more
drugs are likewise bound to the polyvalent linkers (but not to the receptor)
and are capable of affecting the metabolism of the cell to which the ligand
binds. Because we agree with Appellants that a person of ordinary skill in
the art would recognize the functional differences of the terms, as recited in
claim 1, and as disclosed by the Specification, we reverse the Examiner's
rejection of claim 1.
B. Rejection of claim 1 under 35 U.S.C. § 103(a) over Vlahov and
Russell-Jones
Issue
Appellants argue that the Examiner erred in combining the references
because Russell-Jones teaches away from the claimed invention. App. Br.
10.
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Analysis
Appellants argue that Vlahov teaches conjugates having a general
formula V-L-D, which contain a vitamin receptor binding moiety (V), a
bivalent linker (L), and a single drug (D). App. Br. 10 (citing Vlahov 2-3).
According to Appellants, the "bivalent linker" of Vlahov, similar to the
Appellants' claimed "polyvalent linker" is based on small molecule
structures that cannot reasonably be regarded as "polymeric" in the sense
taught by Russell-Jones. Id. Appellants also point out that the Examiner has
acknowledged that Vlahov neither teaches nor or suggests incorporating
"two or more drugs" into the conjugates described therein, as required by
claim 1. Id. at 1 0-11.
Appellants assert that Russell-Jones teaches a folate-containing
polymer complex having the general formula (folate-Q)n-P-(Q'-A)m, where
Q and Q' are independently either a covalent bond or a spacer compound, P
is a pharmaceutically acceptable polymer, and A is a pharmaceutically active
substance. App. Br. 11 (citing Russell-Jones 3). Appellants note that
Russell-Jones teaches that the variable "m" ranges between 1 and 1000. Id.
Therefore, Appellants argue, if m is 2 or greater, the polymer complex
described in Russell-Jones will contain two or more pharmaceutically active
substances (i.e., drugs). Id. Appellants assert that, because Vlahov contains
no teaching or suggestion of incorporating "two or more drugs" in its
conjugates, the Examiner has cited Russell-Jones as teaching a complex
containing more than one drug. Id.
However, argue Appellants, Russell-Jones makes a clear distinction
between its polymeric linkers and nonpolymeric, small molecule linkers of
the type taught by Vlahov. App. Br. 11. Furthermore, Appellants contend,
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Russell-Jones characterizes conjugates containing non-polymeric, small
molecule linkers of the type described in Vlahov as having "major
limitations" and as being "undesirable." Id. By way of example, Appellants
point to Russell-Jones' teaching that:
Two major limitations to the use of folate to target to tumor cells
is that the dose deliverable is small, i.e.[,] one molecule of drug
for each molecule of folate, and that the majority of the folate-
drug complexes are very small and as such are excreted in the
kidneys and re-absorbed in the proximal tubules, thus leading to
undesirable accumulation of folate-drug complexes in the kidney
Russell-Jones 2.
Appellants explain that, to overcome these limitations associated with
small complexes, Russell-Jones advocates instead for the use of polymeric
backbones as opposed to small molecule (i.e., non-polymeric) backbones.
App. Br. 11. Appellants point to pages 2 and 3 of Russell-Jones, which
teach that:
Surprisingly it has been found by the present inventors that
both of the above-mentioned limitations could be addressed by
producing large molecular weight polymer complexes
incorporating folic acid or analogues thereof and a
pharmaceutically active substance to be delivered. Thus,
amplification can occur by linkage of the pharmaceutical to a
polymer backbone to which a small number of folate molecules
are linked, either subsequently, previously or concurrently. The
large size of the polymer also minimises accumulation of the
folate-drug polymers in the kidneys.
Id. at 11-12.
Therefore, Appellants argue, Russell-Jones expressly discourages a
person of ordinary skill in the art seeking to provide therapeutic folate-
targeted drug conjugates from using small molecule folate-drug conjugates,
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such as the small molecule folate-drug conjugates taught in Vlahov. App.
Br. 12. According to Appellants, a person of ordinary skill in the art, having
comprehended the teachings of Russell-Jones, would not have been
motivated to modify the conjugates of Vlahov to incorporate a plurality of
drugs on the bivalent linker to increase the overall molecular weight of the
conjugate as proposed by the Examiner but, rather, would more likely have
been motivated to substitute the small molecule linkers of Vlahov with the
allegedly more effective polymeric linkers advocated in Russell-Jones. Id.
Appellants argue that, because Russell-Jones expressly warns against
using small molecule folate-drug conjugates because they are expected to
accumulate undesirably in the kidney and, because Vlahov is silent on the
subject of accumulation of small molecule folate-drug conjugates in the
kidney, it would not have been obvious to a person of ordinary skill in the
art to modify the conjugates of Vlahov to include multiple drugs, as
described in Russell-Jones. App. Br. 12. Rather, Appellants contend, based
upon the teachings of Russell-Jones, an artisan of ordinary skill would have
been led to the conclusion that attaching multiple drugs to the small
molecule folate-drug conjugates described in Vlahov would merely cause a
greater degree of accumulation of drug in non-target kidney tissue due to the
increased number of drugs, thereby exacerbating the undesirable
accumulation of such small molecule conjugates in non-target tissues. Id.
The Examiner acknowledges that Russell-Jones teaches that the two
major limitations to the use of folate to target tumor cells is that the dose
deliverable is small, i.e., one molecule of drug for each molecule of folate,
and that majority of the folate-drug complexes are very small and as such are
excreted in the kidneys and re-absorbed in the proximal tubules. Ans. 13.
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The Examiner finds that Russell-Jones teaches that its conjugates
advantageously increase the amount of pharmaceutical agent which can be
delivered via the folate uptake mechanism. Id. at 13-14. Therefore, the
Examiner concludes, it would have been obvious to a person of ordinary
skill in the art to have added at least another drug to the conjugates of
Vlahov, because it would advantageously increase the amount of therapeutic
agent that can be delivered via the folate uptake mechanism. Id. at 14.
The Examiner also concludes that a person of ordinary skill would have had
a reasonable expectation of success in combining the teachings of the
references, because Vlahov teaches that the conjugates are suitable for the
treatment of pathogenic cell populations expressing the folate receptor. Id.
The Examiner further finds that Russell-Jones also teaches
amplification of folate conjugates by the use of a polymer linker. Ans. 14.
However, the Examiner finds that Russell-Jones teaches that amplification
occurs by increasing the molecular weight of the conjugate has a whole:
consequently the folate conjugates of Russell-Jones have less accumulation
in the kidneys. Id.
We are not persuaded by Appellants' arguments. It is undisputed by
both Appellants and the Examiner that Vlahov teaches a drug delivery
system comprising a single receptor-binding moiety, a linker that
corresponds to at least one of Appellants' claimed polyvalent linkers, and a
drug. Russell-Jones teaches:
According to a first aspect of the present invention there is
provided a polymer complex having the general formula:
(folate-Q)n-P-(Q'-A)m
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wherein, folate, or an analogue thereof, is a targeting
molecule which will bind to a natural folate receptor, preferably
a surface folate receptor on a tumor or cancer cell; n, the molar
substitution ration of folate in the complex, is in the range from
1.0 to 50.0, preferably from 1.0 to 1.5;
P is a pharmaceutically acceptable polymer;
A is a pharmaceutically active substance;
m, the molar substitution ratio of A in the complex, is in
the range from 1.0 to 1000, preferably from 2 to 200, more
preferably from 10 to 100; and
Q and Q' are independently a covalent bond, or a spacer
compound linking folate, P and A by covalent bonds.
Russell-Jones 3. In other words, Russell-Jones expressly teaches, where n =
1 and m 2: 2, a ligand and multiple drugs are covalently bound by a linker,
i.e.:
A receptor binding drug delivery conjugate comprising:
(a) a receptor binding moiety;
(b) a polyvalent linker; and
( c) two or more drugs, or analogs or derivatives thereof;
wherein the receptor binding moiety is covalently linked to the
polyvalent linker;
the two or more drugs, or analogs or derivatives thereof, are
covalently linked to the polyvalent linker
as recited in claim 1.
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Russell-Jones teaches the use of "polymers" as linker molecules, but
does not expressly teach the linkers recited in claim 1 ( the Examiner teaches
that these are taught by Vlahov). However, claim 1 recites, among its listed
linker molecules, at least:
which has repeating subunits n, and which could reasonably be interpreted,
by an artisan of ordinary skill, as being polymeric. 3
Furthermore, we note that the language of claim 1, which recites the
claim word "comprising" does not exclude a composition of multiple
ligands, linkers, and or/drugs. Use of the transition "comprising" in the
language of a claim "creates a presumption ... that the claim does not
exclude additional, unrecited elements." Crystal Semiconductor Corp. v.
TriTech Microelectronics Int'!, Inc., 246 F.3d 1336, 1348 (Fed. Cir. 2001).
In other words, the scope of the claim does not exclude "multiple linkers
covalently attached to each other," each attached to a drug and/or a receptor
binding moiety, as expressly taught by Russell-Jones. Spec. 2; See Spec. 4
("In one variation, more than one receptor binding ligand is included in the
drug delivery conjugates described herein"). And even if such were the
case, Russell-Jones nevertheless expressly teaches such a schema in the
passage from page 2 quoted supra.
3 Polymer is defined as, "a chemical compound or mixture of compounds
formed by polymerization and consisting essentially of repeating structural
units." https://www.merriam-webster.com/dictionary/polymer
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With respect to Appellants' argument that Russell-Jones teaches away
from Appellants' claim 1, we disagree. As we have explained, both the
language of claim 1 and the compositions taught by Russell-Jones include
within their scope the type of larger molecules less likely to accumulate in
the kidneys of their disclosures. We have explained that Russell-Jones
teaches, inter alia, a single receptor-binding moiety, a linker, and two or
more drugs. Such a molecule, being larger that the single receptor-linker-
drug molecule of Vlahov, falls within the teachings of Russell-Jones and the
disclosures of the Specification, and Appellants adduce no evidence that
such a molecule would possess the drawbacks taught by Russell-Jones. And
again, nothing in the language of claim 1 restricts the claim to a single
receptor moiety, a single linker, and multiple drugs, the claim term
"comprising" includes within the scope of the claim multiple receptor-
binding moieties, linkers, and drugs.
We consequently affirm the Examiner's rejection of claim 1.
C. Rejection of claims 1 and 53-70 under 35 U.S.C. § 103(a) over
Vlahov, Russell-Jones, and Matulic-Adamic
Appellants rely upon the arguments presented with respect to claim 1
supra, that the Examiner improperly combined the teachings of Vlahov and
Matulic-Adamic. App. Br. 13. Therefore, Appellants argue, the
combination ofVlahov and Matulic-Adamic (excluding Russell-Jones)
neither teach nor suggests all of the limitations of claim 1.
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As we have explained above, we reject Appellants' argument that
Vlahov and Russell-Jones cannot be properly combined. Consequently, we
affirm the Examiner's rejection of the claims upon this ground.
DECISION
The Examiner's rejection of claim 1 under 35 U.S.C. § 112, second
paragraph, is reversed.
The Examiner's rejection of claims 1 and 53-70 under 35 U.S.C.
§ 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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