MILLENNIUM PHARMACEUTICALS scores win at CAFC in '446 (Velcade® ) case; Judge Newman explicates obviousness
The case pertains to the chemical compound D-mannitol
N-(2-pyrazine)carbonyl-L-phenylalanine-Lleucine
boronate, described in the text
The mannitol
ester of bortezomib acts as a “prodrug,” a compound that
converts to or releases the active pharmaceutical ingredient
upon administration to a patient. This discovery is
described and claimed in the ’446 Patent.
The ensuing drug product (Velcade®) became “a cancer
treatment that changed the decades-old standard of
care for multiple myeloma and has saved thousands of
lives.
The outcome of the CAFC decision:
On review of the record and the applicable law, we
conclude that the district court erred in the Sandoz litigation
and that invalidity was not established. We reverse
and enter judgment in favor of Millennium in the Sandoz
litigation. We also vacate the district court’s judgment in
the action between Millennium, Teva, and Apotex based
on our decision in the Sandoz litigation and remand that
action for further proceedings.
There is a Kansas connection:
The inventor of the ’446 Patent was associated with
the National Cancer Institute and the University of
Kansas, and was consulted by Dr. Adams after years of
unsuccessful attempts to solve formulation and stability
problems with bortezomib. Despite preparing approximately
twenty-five different liquid formulations, these
efforts encountered the same stability and solubility
problems as had other researchers attempting to solve
this problem.
After failing to develop a viable liquid formulation, researchers
began work on a lyophilized formulation for
injection. The process of lyophilization (freeze-drying) is
not intended to change the chemical structure of the
active pharmaceutical ingredient. After experimenting
with multiple variables that affect the lyophilization
process, including solvents and bulking agents, researchers
produced a promising lyophilized formulation using
mannitol, a known bulking agent. It was discovered that
the reason for the dramatic improvement in dissolution
and stability for this formulation was the formation of a
new chemical compound during lyophilization: the
claimed ester of bortezomib and mannitol. The mannitol
ester of bortezomib acts as a “prodrug,” a compound that
converts to or releases the active pharmaceutical ingredient
upon administration to a patient. This discovery is
described and claimed in the ’446 Patent.
District court reasoning:
The district court held that the claims were obvious
because they were the inherent result of an allegedly
obvious process, viz., lyophilizing bortezomib in the presence
of the bulking agent mannitol. Millennium argued
that a person of ordinary skill would avoid lyophilization
in developing a formulation involving bortezomib because
“bortezomib was known to be unstable even in the dry
state as a freestanding solid compound.” Dist. Ct. Op. *6.
The court was not persuaded by this argument and instead
relied on the testimony of Sandoz’s witness, Dr.
Repta, to find that, as of the ’446 Patent’s priority date,
lyophilization “was well-known in the field of formulation”
and that it was considered an obvious alternative “when a
liquid formulation provided limited success.” Id.
The district court did not find that the prior art
taught or suggested that the claimed new compound
would be formed, or taught or suggested making the
claimed new compound by any method, or taught or
suggested that this new compound would have the properties
of stability, solubility, and dissociability that it
exhibited. No reference taught or suggested reacting
bortezomib with mannitol, and no reference hinted that
such an esterification reaction might occur during lyophilization.
No reference taught or suggested that the product
of such lyophilization would be a new chemical
compound that would solve the problems that had inhibited
development of bortezomib in oncology. H
(...)
On the evidence of objective indicia of obviousness,
the district court found that Millennium did not establish
unexpected results because it did not compare the claimed
invention to a glycerol ester of bortezomib. Id. at *9. The
court also rejected long-felt need as objective evidence of
non-obviousness, stating that “the lyophilized mannitol
ester of bortezomib did not solve any problem having
persisted over a long period of time without resolution by
the prior art.” Id. at *10 (quoting Hitachi Koki Co. v.
Doll, 620 F. Supp. 2d 4, 30 (D.D.C. 2009)).
The CAFC said:
Recognizing our obligation to give deference to a district
court’s greater familiarity with the record and authority
to reach factual conclusions therefrom, we
conclude that the district court erred in its evaluation of
obviousness. See KSR Int’l Co. v. Teleflex Inc., 550 U.S.
398, 419-20 (2007) (the question of law is whether the
prior art rendered the invention obvious). In the case at
bar, the question is whether a person of ordinary skill,
seeking to remedy the known instability and insolubility
and to produce an efficacious formulation of bortezomib,
would obviously produce the D-mannitol ester of bortezomib,
a previously unknown compound.
The prior art contains no teaching or suggestion of
this new compound, or that it would form during lyophilization.
Sandoz identifies no reference or combination of
references that shows or suggests a reason to make the
claimed compound. No reference teaches or suggests that
such a new compound would have the long-sought properties
of stability and solubility, and sufficiently dissociate
to release bortezomib at an effective rate in the bloodstream,
all critical to effective use for treating multiple
myeloma.
The D-mannitol ester of bortezomib is a new compound
with distinct chemical properties. We consider
whether the prior art “would have supplied one of ordinary
skill in the art with a reason or motivation to modify
a lead compound to make the claimed compound with a
reasonable expectation of success.” Otsuka Pharm. Co.,
Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012);
see also Bristol-Myers Squibb Co. v. Teva Pharm. USA,
Inc., 752 F.3d 967, 973 (Fed. Cir. 2014) (“To establish
obviousness in cases involving new chemical compounds,
the accused infringer must identify some reason that
would have led a chemist to modify a known compound.”);
In re Rosuvastatin Calcium Patent Litig., 703 F.3d 511,
518 (Fed. Cir. 2012) (affirming district court conclusion
that “the Defendants did not demonstrate the required
motivation for selecting Sandoz Compound 1b as a lead
compound”). The parties agree that bortezomib is the
proper lead compound for this analysis. It is not disputed
that the Velcade® compound provided unexpected properties,
solving the problems that accompanied bortezomib.
The district court clearly erred in its obviousness
analysis. There is no teaching or suggestion in the references
to produce the claimed mannitol ester. No reference
shows or suggests ester formation at freeze-drying conditions,
or that any such ester might solve the problems of
instability and insolubility of the free acid while dissociating
rapidly in the bloodstream. No reference provides a
reason to make the mannitol ester of bortezomib.
(...)
Although mannitol was a known
bulking agent, and lyophilization was a known method of
drug formulation, nothing on the record teaches or suggests
that a person of ordinary skill should have used
mannitol as part of a synthetic reaction to make an ester
through lyophilization. A result is obvious when it is “the
natural result flowing from the operation as taught,” or a
“property that is necessarily present” when applying a
process disclosed in the prior art. Par Pharm., Inc. v. TWI
Pharm., Inc., 773 F.3d 1186, 1195 (Fed. Cir. 2014) (emphasis
omitted) (first quoting In re Oelrich, 666 F.2d 578,
581 (CCPA 1981); then quoting Alcon Research, Ltd. v.
Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012), and In
re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009)). Sandoz
failed to show that it was obvious to use mannitol to make
an ester during lyophilization, or that the ester would
solve the problems experienced with bortezomib.
Nobel laureate H.C. Brown appears in a footnote:
Herbert C. Brown and J.V.N. Vara Prasad, Chiral
Synthesis via Organoboranes. 9. Crystalline “Chelates”
from Borinic and Boronic Esters. A Simple Procedure for
Upgrading Borinates and Boronates to Materials Approaching
100% Optical Purity, 51 J. ORGANIC CHEMISTRY
4526 (1986)
Yes, the CAFC discussed inherency:
The district court also clearly erred in its consideration
of inherency. “A party must . . . meet a high standard
in order to rely on inherency to establish the existence of
a claim limitation in the prior art in an obviousness
analysis.” Par Pharm., 773 F.3d at 1195–96. “The mere
fact that a certain thing may result from a given set of
circumstances is not sufficient” to render the result inherent.
In re Oelrich, 666 F.2d at 581 (quoting Hansgirg v.
Kemmer, 102 F.2d 212, 214 (CCPA 1939)).
The district court stated that Millennium “conceded
as a matter of law that the ester is the ‘natural result’ of
freeze-drying bortezomib with mannitol.” Dist. Ct. Op. *8.
However, “[t]he inventor’s own path itself never leads to a
conclusion of obviousness; that is hindsight. What matters
is the path that the person of ordinary skill in the art
would have followed, as evidenced by the pertinent prior
art.” Otsuka, 678 F.3d at 1296. This oft-cited principle is
explained in, for example, In re Kratz, 592 F.2d 1169,
1175 (CCPA 1979):
However, making weight of the method appellant
used in finding the invention is beside the point.
The last sentence of 35 U.S.C. § 103, with great
clarity, excludes such methodology in stating that
“(p)atentability shall not be negatived by the
manner in which the invention was made.”
See also, e.g., Life Techs., Inc. v. Clontech Labs., Inc., 224
F.3d 1320, 1325 (Fed. Cir. 2000) (“[T]he path that leads
an inventor to the invention is expressly made irrelevant
to patentability by statute.”).
Sandoz argues that although lyophilization in the
presence of mannitol produced an unexpected result, the
result was “inevitable” and thus “inherent,” and thus not
“inventive.” Sandoz Br. at 1, 12-17. However, invention
is not a matter of what the inventor intended when the
experiment was performed; obviousness is measured
objectively in light of the prior art, as viewed by a person
of ordinary skill in the field of the invention. “Those
charged with determining compliance with 35 U.S.C.
§ 103 are required to place themselves in the minds of
those of ordinary skill in the relevant art at the time the
invention was made, to determine whether that which is
now plainly at hand would have been obvious at such
earlier time.” Interconnect Planning Corp. v. Feil, 774
F.2d 1132, 1138 (Fed. Cir. 1985). No expert testified that
they foresaw, or expected, or would have intended, the
reaction between bortezomib and mannitol, or that the
resulting ester would have the long-sought properties and
advantages.
And of secondary considerations:
We conclude finally that the district court clearly
erred in its examination of the objective indicia of unexpected
results and long-felt need. All of the Graham
factors must be considered, including the objective indicia
when present, before any conclusion regarding obviousness
is reached. In re Cyclobenzaprine, 676 F.3d at 1075–
76 (citation omitted); Gambro Lundia AB v. Baxter
Healthcare Corp., 110 F.3d 1573, 1579 (Fed. Cir. 1997);
see Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520
F.3d 1358, 1365 (Fed. Cir. 2008) (stating that objective
indicia are “not just a cumulative or confirmatory part of
the obviousness calculus but constitute[] independent
evidence of nonobviousness”).
Evidence of objective indicia “can be the most probative
evidence of nonobviousness in the record,” and objective
indicia enable “the court to avert the trap of
hindsight.” Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d
1346, 1358 (Fed. Cir. 2013) (quoting Crocs, Inc. v. Int’l
Trade Comm’n, 598 F.3d 1294, 1310 (Fed. Cir. 2010)).
These indicia cannot be set aside in the analysis of obviousness.
The outcome:
The district
court’s judgment of invalidity is reversed, and judgment is
entered in favor of Millennium as to the Sandoz defendants.
We remand for any appropriate further proceedings
in that action.
The judgment between Millennium and Apotex and
Teva is vacated, and remanded for further proceedings in
those actions.
link: http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/15-2066.Opinion.7-13-2017.1.PDF
**Separately, from blawgsearch on 17 July 17:
N-(2-pyrazine)carbonyl-L-phenylalanine-Lleucine
boronate, described in the text
The mannitol
ester of bortezomib acts as a “prodrug,” a compound that
converts to or releases the active pharmaceutical ingredient
upon administration to a patient. This discovery is
described and claimed in the ’446 Patent.
The ensuing drug product (Velcade®) became “a cancer
treatment that changed the decades-old standard of
care for multiple myeloma and has saved thousands of
lives.
The outcome of the CAFC decision:
On review of the record and the applicable law, we
conclude that the district court erred in the Sandoz litigation
and that invalidity was not established. We reverse
and enter judgment in favor of Millennium in the Sandoz
litigation. We also vacate the district court’s judgment in
the action between Millennium, Teva, and Apotex based
on our decision in the Sandoz litigation and remand that
action for further proceedings.
There is a Kansas connection:
The inventor of the ’446 Patent was associated with
the National Cancer Institute and the University of
Kansas, and was consulted by Dr. Adams after years of
unsuccessful attempts to solve formulation and stability
problems with bortezomib. Despite preparing approximately
twenty-five different liquid formulations, these
efforts encountered the same stability and solubility
problems as had other researchers attempting to solve
this problem.
After failing to develop a viable liquid formulation, researchers
began work on a lyophilized formulation for
injection. The process of lyophilization (freeze-drying) is
not intended to change the chemical structure of the
active pharmaceutical ingredient. After experimenting
with multiple variables that affect the lyophilization
process, including solvents and bulking agents, researchers
produced a promising lyophilized formulation using
mannitol, a known bulking agent. It was discovered that
the reason for the dramatic improvement in dissolution
and stability for this formulation was the formation of a
new chemical compound during lyophilization: the
claimed ester of bortezomib and mannitol. The mannitol
ester of bortezomib acts as a “prodrug,” a compound that
converts to or releases the active pharmaceutical ingredient
upon administration to a patient. This discovery is
described and claimed in the ’446 Patent.
District court reasoning:
The district court held that the claims were obvious
because they were the inherent result of an allegedly
obvious process, viz., lyophilizing bortezomib in the presence
of the bulking agent mannitol. Millennium argued
that a person of ordinary skill would avoid lyophilization
in developing a formulation involving bortezomib because
“bortezomib was known to be unstable even in the dry
state as a freestanding solid compound.” Dist. Ct. Op. *6.
The court was not persuaded by this argument and instead
relied on the testimony of Sandoz’s witness, Dr.
Repta, to find that, as of the ’446 Patent’s priority date,
lyophilization “was well-known in the field of formulation”
and that it was considered an obvious alternative “when a
liquid formulation provided limited success.” Id.
The district court did not find that the prior art
taught or suggested that the claimed new compound
would be formed, or taught or suggested making the
claimed new compound by any method, or taught or
suggested that this new compound would have the properties
of stability, solubility, and dissociability that it
exhibited. No reference taught or suggested reacting
bortezomib with mannitol, and no reference hinted that
such an esterification reaction might occur during lyophilization.
No reference taught or suggested that the product
of such lyophilization would be a new chemical
compound that would solve the problems that had inhibited
development of bortezomib in oncology. H
(...)
On the evidence of objective indicia of obviousness,
the district court found that Millennium did not establish
unexpected results because it did not compare the claimed
invention to a glycerol ester of bortezomib. Id. at *9. The
court also rejected long-felt need as objective evidence of
non-obviousness, stating that “the lyophilized mannitol
ester of bortezomib did not solve any problem having
persisted over a long period of time without resolution by
the prior art.” Id. at *10 (quoting Hitachi Koki Co. v.
Doll, 620 F. Supp. 2d 4, 30 (D.D.C. 2009)).
The CAFC said:
Recognizing our obligation to give deference to a district
court’s greater familiarity with the record and authority
to reach factual conclusions therefrom, we
conclude that the district court erred in its evaluation of
obviousness. See KSR Int’l Co. v. Teleflex Inc., 550 U.S.
398, 419-20 (2007) (the question of law is whether the
prior art rendered the invention obvious). In the case at
bar, the question is whether a person of ordinary skill,
seeking to remedy the known instability and insolubility
and to produce an efficacious formulation of bortezomib,
would obviously produce the D-mannitol ester of bortezomib,
a previously unknown compound.
The prior art contains no teaching or suggestion of
this new compound, or that it would form during lyophilization.
Sandoz identifies no reference or combination of
references that shows or suggests a reason to make the
claimed compound. No reference teaches or suggests that
such a new compound would have the long-sought properties
of stability and solubility, and sufficiently dissociate
to release bortezomib at an effective rate in the bloodstream,
all critical to effective use for treating multiple
myeloma.
The D-mannitol ester of bortezomib is a new compound
with distinct chemical properties. We consider
whether the prior art “would have supplied one of ordinary
skill in the art with a reason or motivation to modify
a lead compound to make the claimed compound with a
reasonable expectation of success.” Otsuka Pharm. Co.,
Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012);
see also Bristol-Myers Squibb Co. v. Teva Pharm. USA,
Inc., 752 F.3d 967, 973 (Fed. Cir. 2014) (“To establish
obviousness in cases involving new chemical compounds,
the accused infringer must identify some reason that
would have led a chemist to modify a known compound.”);
In re Rosuvastatin Calcium Patent Litig., 703 F.3d 511,
518 (Fed. Cir. 2012) (affirming district court conclusion
that “the Defendants did not demonstrate the required
motivation for selecting Sandoz Compound 1b as a lead
compound”). The parties agree that bortezomib is the
proper lead compound for this analysis. It is not disputed
that the Velcade® compound provided unexpected properties,
solving the problems that accompanied bortezomib.
The district court clearly erred in its obviousness
analysis. There is no teaching or suggestion in the references
to produce the claimed mannitol ester. No reference
shows or suggests ester formation at freeze-drying conditions,
or that any such ester might solve the problems of
instability and insolubility of the free acid while dissociating
rapidly in the bloodstream. No reference provides a
reason to make the mannitol ester of bortezomib.
(...)
Although mannitol was a known
bulking agent, and lyophilization was a known method of
drug formulation, nothing on the record teaches or suggests
that a person of ordinary skill should have used
mannitol as part of a synthetic reaction to make an ester
through lyophilization. A result is obvious when it is “the
natural result flowing from the operation as taught,” or a
“property that is necessarily present” when applying a
process disclosed in the prior art. Par Pharm., Inc. v. TWI
Pharm., Inc., 773 F.3d 1186, 1195 (Fed. Cir. 2014) (emphasis
omitted) (first quoting In re Oelrich, 666 F.2d 578,
581 (CCPA 1981); then quoting Alcon Research, Ltd. v.
Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012), and In
re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009)). Sandoz
failed to show that it was obvious to use mannitol to make
an ester during lyophilization, or that the ester would
solve the problems experienced with bortezomib.
Nobel laureate H.C. Brown appears in a footnote:
Herbert C. Brown and J.V.N. Vara Prasad, Chiral
Synthesis via Organoboranes. 9. Crystalline “Chelates”
from Borinic and Boronic Esters. A Simple Procedure for
Upgrading Borinates and Boronates to Materials Approaching
100% Optical Purity, 51 J. ORGANIC CHEMISTRY
4526 (1986)
Yes, the CAFC discussed inherency:
The district court also clearly erred in its consideration
of inherency. “A party must . . . meet a high standard
in order to rely on inherency to establish the existence of
a claim limitation in the prior art in an obviousness
analysis.” Par Pharm., 773 F.3d at 1195–96. “The mere
fact that a certain thing may result from a given set of
circumstances is not sufficient” to render the result inherent.
In re Oelrich, 666 F.2d at 581 (quoting Hansgirg v.
Kemmer, 102 F.2d 212, 214 (CCPA 1939)).
The district court stated that Millennium “conceded
as a matter of law that the ester is the ‘natural result’ of
freeze-drying bortezomib with mannitol.” Dist. Ct. Op. *8.
However, “[t]he inventor’s own path itself never leads to a
conclusion of obviousness; that is hindsight. What matters
is the path that the person of ordinary skill in the art
would have followed, as evidenced by the pertinent prior
art.” Otsuka, 678 F.3d at 1296. This oft-cited principle is
explained in, for example, In re Kratz, 592 F.2d 1169,
1175 (CCPA 1979):
However, making weight of the method appellant
used in finding the invention is beside the point.
The last sentence of 35 U.S.C. § 103, with great
clarity, excludes such methodology in stating that
“(p)atentability shall not be negatived by the
manner in which the invention was made.”
See also, e.g., Life Techs., Inc. v. Clontech Labs., Inc., 224
F.3d 1320, 1325 (Fed. Cir. 2000) (“[T]he path that leads
an inventor to the invention is expressly made irrelevant
to patentability by statute.”).
Sandoz argues that although lyophilization in the
presence of mannitol produced an unexpected result, the
result was “inevitable” and thus “inherent,” and thus not
“inventive.” Sandoz Br. at 1, 12-17. However, invention
is not a matter of what the inventor intended when the
experiment was performed; obviousness is measured
objectively in light of the prior art, as viewed by a person
of ordinary skill in the field of the invention. “Those
charged with determining compliance with 35 U.S.C.
§ 103 are required to place themselves in the minds of
those of ordinary skill in the relevant art at the time the
invention was made, to determine whether that which is
now plainly at hand would have been obvious at such
earlier time.” Interconnect Planning Corp. v. Feil, 774
F.2d 1132, 1138 (Fed. Cir. 1985). No expert testified that
they foresaw, or expected, or would have intended, the
reaction between bortezomib and mannitol, or that the
resulting ester would have the long-sought properties and
advantages.
And of secondary considerations:
We conclude finally that the district court clearly
erred in its examination of the objective indicia of unexpected
results and long-felt need. All of the Graham
factors must be considered, including the objective indicia
when present, before any conclusion regarding obviousness
is reached. In re Cyclobenzaprine, 676 F.3d at 1075–
76 (citation omitted); Gambro Lundia AB v. Baxter
Healthcare Corp., 110 F.3d 1573, 1579 (Fed. Cir. 1997);
see Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520
F.3d 1358, 1365 (Fed. Cir. 2008) (stating that objective
indicia are “not just a cumulative or confirmatory part of
the obviousness calculus but constitute[] independent
evidence of nonobviousness”).
Evidence of objective indicia “can be the most probative
evidence of nonobviousness in the record,” and objective
indicia enable “the court to avert the trap of
hindsight.” Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d
1346, 1358 (Fed. Cir. 2013) (quoting Crocs, Inc. v. Int’l
Trade Comm’n, 598 F.3d 1294, 1310 (Fed. Cir. 2010)).
These indicia cannot be set aside in the analysis of obviousness.
The outcome:
The district
court’s judgment of invalidity is reversed, and judgment is
entered in favor of Millennium as to the Sandoz defendants.
We remand for any appropriate further proceedings
in that action.
The judgment between Millennium and Apotex and
Teva is vacated, and remanded for further proceedings in
those actions.
link: http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/15-2066.Opinion.7-13-2017.1.PDF
**Separately, from blawgsearch on 17 July 17:
posted by Lawrence B. Ebert at 9:41 AM
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