Millennium Pharmaceuticals Inc. v. Sandoz Inc., et al
MEMORANDUM OPINION. Signed by Judge Gregory M. Sleet on 8/20/2015. (mdb)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
MILLENNIUM PHARMACEUTICALS, INC.,
SANDOZ INC., et al.,
C.A. No. 12-1011-GMS
In this patent infringement action, the plaintiff Millennium Pharmaceuticals, Inc.
("Millennium") alleges that Abbreviated New Drug Applications ("ANDAs") filed by the
defendants Sandoz Inc. ("Sandoz"), Accord Healthcare, Inc. ("Accord"), and Actavis LLC
("Actavis") (collectively, "the defendants") infringe claims 20, 31, 49, and 53 of U.S. Patent No.
6,713,446 ("the '446 patent"). 1 (D.I. 1. 2 ) The court held a four-day bench trial in this matter on
November 4 through November 7, 2014.
(D.I. 139-42.) Presently before the court are the
parties' post-trial proposed findings of fact and conclusions of law concerning the validity of the
'446 patent, specifically whether the asserted claims of the '446 are invalid as obvious under 35
U.S.C. § 103. (D.I. 132, 133.)
The parties filed stipulations dismissing allegations that the defendants infringed U.S. Patent No. 6,958,319
on November 3, 2014. (See D.I. 122; 123; 124.)
All citations to the court's docket refer to Civil Action Number 12-1011-GMS.
Millennium is a corporation organized and ex1stmg under the laws of the State of
Delaware, with its principal place of business at 40 Landsdowne Street, Cambridge,
Sandoz is a corporation organized and existing under the laws of the State of Colorado,
with its principal place of business at 56 Carnegie Center, Suite 400, Princeton, New Jersey.
Accord is a corporation organized and existing under the laws of the State of North
Carolina, with its principal place of business at 1009 Slater Road, Suite 210B, Durham, North
Actavis is a limited liability company organized and existing under the laws of the State of
Delaware, with its principal place of business at Morris Corporate Center III, 400 Interpace
Parkway, Parsippany, New Jersey.
VELCADE® (bortezomib) for Injection is a proteasome inhibitor used in the treatment of
patients with multiple myeloma and patients with mantle cell lymphoma who have received at
least one prior therapy.
In 2003, the Food and Drng Administration ("FDA") granted "accelerated approval" to
New Drng Application No. 21-602 for VELCADE® for Injection, for the treatment by intravenous
administration of patients with multiple myeloma who have received at least two prior therapies
and have demonstrated disease progression on the last therapy.
VELCADE® for Injection was subsequently approved in 2005 for treatment by
intravenous administration of patients with multiple myeloma who had received at least one prior
therapy; in 2006 for treatment by intravenous administration of patients with mantle cell
lymphoma who had failed at least one prior therapy; in 2008 for frontline treatment by
intravenous administration of patients with multiple myeloma; in 2012 for subcutaneous
administration; and in 2014 for treatment of adult patients with multiple myeloma who had
previously responded to VELCADE® for Injection therapy and relapsed at least six months
following completion of prior VELCADE® for Injection treatment.
The '446 patent has been listed in connection with VELCADE®for Injection in the FDA's
publication, Approved Drug Products with Therapeutic Equivalence Evaluations, referred to as
the "Orange Book."
These facts are drawn primarily from the parties' jointly submitted statement of uncontested facts. (See
U.S. Patent No. 5,780,454 ("the '454 patent"), among others, is also listed in the Orange
Book in connection with VELCADE® for Injection. The '454 patent, entitled "Boronic Ester and
Acid Compounds," issued on July 14, 1998, is assigned to Millennium, and will expire on May 3,
2017. The '454 patent is prior art to the '446 patent and is of record in the prosecution of the '446
Millennium sells VELCADE® for Injection in the United States.
The '446 patent, entitled "Formulation ofBoronic Acid Compounds," issued on March 30,
2004, naming Shanker Lal Gupta as the inventor. The '446 patent claims priority to Provisional
Application No. 60/264, 160, filed on January 25, 2001 ("the '160 provisional").
A Certificate of Correction issued for the '446 patent on September 6, 2005.
The '446 patent is assigned to the United States of America as Represented by the
Secretary of Health and Human Services.
Millennium holds an exclusive worldwide license to the '446 patent for the research,
development, and manufacture of Bortezomib for distribution, sale and use in oncology disease
states. Pursuant to its license, Millennium has the right to bring suit for infringement and defend
invalidity counterclaims in its own name and own behalf.
1. The Asserted Claims
Millennium asserts claims 20, 31, 49, and 53 ("Asserted Claims") of the '446 patent.
'446 Patent, Claim 20
Claim 20 of the '446 patent is directed to directed to lyophilized mannitol boronate ester
compounds, including the lyophilized mannitol ester ofbortezomib.
'446 Patent, Claim 31
Claim 31 of the '446 patent is directed to preparing the lyophilized mannitol ester of
bortezomib by lyophilizing a mixture of water, bortezomib and mannitol.
'446 Patent, Claim 49
Claim 49 of the '446 patent is directed to a lyophilized cake comprising the lyophilized
mannitol ester of bortezomib.
The parties agreed to refer to the '454 patent as the "Adams patent" because the number is similar to the
patent-in-suit. Tr. 47.
'446 Patent, Claim 53
Claim 53 of the '446 patent adds to the method of claim 31 the further step of
reconstituting the lyophilized mixture comprising the mannitol ester of bortezomib with a
2. The Accused Products
i. ANDAs Filed by the Defendants
Millennium's VELCADE® for Injection is FDA-approved to treat multiple myeloma and
mantle cell lymphoma. (D.I. 112-1, ifif 11-13.)
Sandoz, Accord, and Actavis filed ANDA Nos. 203654, 204405, and 204332,
respectively, seeking approval for the commercial manufacture, use, and sale of generic versions
ofVELCADE®for Injection. (Id, ifif 16, 20, 25.)
The defendants dispute that any of the asserted claims are valid. (Id.,
ifi! 18, 23, 28.)
The defendants previously entered into stipulations regarding infringement of certain
claims of the '446 patent including the Asserted Claims with the exception of Claim 53, which
relies on induced infringement. (See D.I. 86, 92, 94.) The defendants challenge the alleged
induced infringement of Claim 53. The primary issue presented at trial was obviousness.
In separately-captioned actions, Millennium filed complaints for patent infringement
against Sandoz (C.A. 12-1011-GMS), Accord (12-490-GMS), and Actavis (12-1750-GMS) on
August 2, 2012, November 19, 2012, and December 21, 2012, respectively.
Millennium's actions against Accord and Actavis were consolidated with the Sandoz
action on April 23, 2013. (D.I. 21.)
FINDINGS OF FACT AND CONCLUSIONS OF LAW
The court has subject matter jurisdiction over this matter pursuant to 28 U.S.C. §§ 1331,
1338, and 2201. Venue is proper in this court under 28 U.S.C. §§ 1391 and 1400(b). The court
has considered whether the asserted claims are invalid due to obviousness and, if so, whether the
defendants induced infringement of Claim 53 of the '446 patent. After having reviewed the entire
record in this case, the parties' post-trial submissions, and the applicable law, the court concludes
that the asserted claims of the '446 patent are invalid due to obviousness. 5 The court will
therefore grant the defendants' Rule 52(c) motion. The court's reasoning follows.
The defendants challenge the validity of each of the asserted claims as obvious in light of
the prior art. The court finds, for the reasons that follow, that the defendants have established by
clear and convincing evidence that the asserted claims of the '446 patent are obvious.
While worded differently, each claim has three central elements: (1) freeze-drying
bortezomib, (2) using mannitol, (3) to form a bortezomib-mannitol ester. 6 Tr. 122-25 (Repta).
Millennium asserts an invention date of December 1997 based on the first time that Dr. Valentino
Stella freeze-dried bortezomib with mannitol. 7
Tr. 477 (Stella); PTX-32 at 13-17 (Waugh
Notebook); Tr. 690-91 (Snow).
1. The Legal Standard
35 U.S.C. § 103(a) provides that a patent may not be obtained "if the differences between
the subject matter sought to be patented and the prior art are such that the subject matter as a
whole would have been obvious to a person having ordinary skill in the art." 35 U.S.C. § 103(a).
Obviousness is a question of law that is predicated on several factual inquires. See Richardson-
Vicks v. Upjohn Co., 122 F.3d 1476, 1479 (Fed. Cir. 1997). Specifically, the trier of fact is
directed to assess four considerations: (1) the scope and content of the prior art; (2) the level of
ordinary skill in the art; (3) the differences between the claimed subject matter and the prior art;
and (4) secondary considerations of non-obviousness, such as commercial success, long felt but
Accordingly, the court does not address Millennium's arguments of induced infringement of Claim 53.
The court notes that the defendants' "good-faith belief of invalidity" is not a viable defense to induced infringement,
had the court found the patents valid. See Cammi/ USA, LLC v. Cisco Sys., Inc., 135 S. Ct. 1920 (2015).
In addition to the main three elements, Claim 53 adds the step of "reconstitution," which involves adding
liquid to the freeze-dried cake to put the drug into solution for injection into the patient. DTX-1-012, cl. 53 ('446
patent); Tr. 111 (Repta).
Dr. Stella and his assistant Wanda Waugh were added as inventors after an inventorship suit and decision
in 2012. See infra notes 8, 10.
unsolved need, failure of others, acquiescence of others in the industry that the patent is valid, and
unexpected results. See Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966).
A patent and each of its claims are presumed to be valid. 35 U.S.C. § 282(a). A party
seeking to challenge the validity of a patent based on obviousness must demonstrate by "clear and
convincing evidence" that the invention described in the patent would have been obvious to a
person of ordinary skill in the art at the time the invention was made. Kao Corp. v. Unilever US.,
Inc., 441 F3d 963, 968 (Fed. Cir. 2006) (citation omitted). "Clear and convincing evidence is
evidence that places in the fact finder 'an abiding conviction that the truth of [the] factual
contentions are 'highly probable.'" Alza Corp v. Andrx Pharms., LLC, 607 F. Supp. 2d 614, 631
(D. Del. 2009) (quoting Colorado v. New Mexico, 467 U.S. 310, 316 (1984)). This burden of
proof remains constant, even when a patent invalidity attack relies on the same prior art
previously considered by the PTO. See Sciele Pharma Inc. v. Lupin Ltd., 684 F.3d 1253, 1260
(Fed. Cir. 2012) ("The burden does not suddenly change to something higher-'extremely clear
and convincing evidence' or 'crystal clear and convincing evidence'-simply because the prior
art references were considered by the PTO.") Practically speaking, however, "it may be harder to
meet the clear and convincing burden when the invalidity contention is based upon the same
argument on the same reference that the PTO already considered." Id.
Importantly, in determining what would have been obvious to one of ordinary skill in the
art, the use of hindsight is not permitted. See KSR Int'! Co. v. Teleflex, Inc., 550 U.S. 398, 421
(2007) (cautioning the trier of fact against "the distortion caused by hindsight bias" and
"arguments reliant upon ex post reasoning" in determining obviousness). In KSR, the Supreme
Court rejected the rigid application of the principle that there should be an explicit "teaching,
suggestion, or motivation" in the prior art, the nature of the problem, or the knowledge of a
person having ordinary skill in the art, in order to find obviousness. See KSR, 550 U.S. at 415.
The KSR Court acknowledged, however, the importance of identifying "'a reason that would have
prompted a person of ordinary skill in the relevant field to combine the elements in the way the
claimed new invention does' in an obviousness determination."
Takeda Chem. Indus. v.
Alphapharm Pty. Ltd, 492 F.3d 1350, 1356-57 (Fed. Cir. 2007) (quoting KSR, 550 U.S. at 418).
"Obviousness does not require absolute predictability of success" but, rather, requires "a
reasonable expectation of success." See Medichem, S.A. v. Rolado, S.L., 437 F.3d 1157, 1165
(Fed. Cir. 2006) (quoting Jn re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988)). To this end,
obviousness "cannot be avoided simply by a showing of some degree of unpredictability in the art
so long as there was a reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364 (Fed. Cir. 2007). Moreover, while the Federal Circuit has noted that pharmaceuticals
can be an "unpredictable art," to the extent that results may be unexpected, it also has recognized
that, per KSR, evidence of a "finite number of identified, predictable solutions" or alternatives
"might support an inference of obviousness." See Eisai Co. v. Dr. Reddy's Labs. Ltd, 533 F.3d
1353, 1359 (Fed. Cir. 2008). Obviousness does not require proof that something is "the best
option, only that it be a suitable option from which the prior art did not teach away." Par Pharm.,
Inc. v. TWJ Pharm., Inc., 773 F.3d 1186, 1198 (Fed. Cir. 2014).
2. The Level of Ordinary Skill in the Art
A person of ordinary skill in the art ("POSA") of the '446 patent would have had a
graduate or undergraduate degree in pharmaceutical sciences or a related field and at least two
years' experience formulating pharmaceutical products. 8
The court's definition is drawn from the testimony of Dr. Arnold Repta. Tr. 104--05. While Dr. Repta's
definition was slightly different than that of Dr. Bradley Anderson and Dr. Roger Snow, all doctors testified that their
opinions on obviousness would not change, regardless of whose definition of a POSA applied. See Tr. I 06, 624, 705.
The court concludes that the parties' definitions ofa POSA do not differ in any meaningful way.
3. The Scope and Content of the Prior Art and Differences Between
the Claimed Subject Matter and the Prior Art
As a preliminary matter, Millennium asserts that the defendants "improperly rely on a host
of prior art references without identifying any specific combination (or single reference) that
purportedly renders the claims of the '446 obvious." (D.I. 132, ir 3.)
The defendants argue that the asserted claims are obvious because the '446 patent claims
the inherent result of an obvious process-namely, that freeze-drying bortezomib with mannitol
produces an ester. (D.I. 133, if 2.) Millennium argues that the defendants failed to prove that a
POSA would have been motivated to modify bortezomib to make the lyophilized mannitol ester.
(D.I. 132, ir 114.)
Specific Combination of References
Millennium argues as a preliminary matter that the defendants' expert, Dr. Arnold Repta,
"did not identify any specific combination of references or any single reference that supposedly
renders the asserted claims obvious, but instead cited 17 references to support his obviousness
A party asserting a patent is invalid for obviousness must prove that one skilled in the art
would have been motivated to combine the claimed references. See Braintree Labs., Inc. v. Novel
Labs. Inc., 749 F.3d 1349, 1359 (Fed. Cir. 2014). There must be a "plausible rational[e] as to
why the prior art references would have worked together." Power-One, Inc. v. Artesyn Techs.,
Inc., 599 F.3d 1343, 1352 (Fed. Cir. 2010).
The court concludes that Dr. Repta's opinion provides appropriate reasoning to support his
determination that the '446 patent is invalid for obviousness. As discussed more fully below, Dr.
Repta properly conducted his obviousness inquiry and addressed how a POSA would have found
the claims obvious based on the art described. Unlike the concerns articulated by the Court in
Braintree, Dr. Repta' s utilization of the references supports a "plausible rationale" as to why the
prior art references would have worked together and, further, clearly articulates how and why a
POSA would have been motivated to lyophilize bortezomib with mannitol to form an ester. See
Bortezomib is Tlte Closest Prior Art
The Adams, or '454, patent provides the sole prior art for the Bortezomib compound.
There is no dispute that it qualifies as relevant prior art.
Millennium's predecessor, ProScript, first applied for a patent on bortezomib in 1995.
DTX-20. The Adams patent disclosed that bortezomib was a potent anti-cancer drug. Tr. 869
(Anderson). As Millennium's expert Dr. Anderson acknowledged, the Adams patent identified
bortezomib as a "very potent, promising lead candidate" with the "highest in-vivo activity" of all
the compounds disclosed in the patent. Tr. 869, 743. The Adams patent not only discloses
bortezomib, but also esters of bortezomib.
Claim 18 expressly claims "pharmaceutically
acceptable salts and esters" of bortezomib. '454 patent, 65: 19-21; Tr. 865 (Anderson). The
Adams patent further claimed "pharmaceutical compositions" of the claimed esters, including the
bortezomib esters. '454 patent, 65:22-35, 66:28-30; Tr. 875-76, 873 (Anderson). The Adams
patent discloses and claims the use of "prodrugs." Tr. 876-77. A "prodrug"-like the claimed
mannitol ester of bortezomib-is a drug compound "that ... upon administration rapidly releases
the active agent." Tr. 256 (Repta); see also Tr. 256 (Repta); Tr. 766 (Anderson).
Decision to Lyopliilize Bortezomib Was Obvious
Millennium asserts that in light of the prior art a person of ordinary skill would avoid
lyophilization in attempting to develop a formulation involving boronic acid compounds. (D.I.
132, irir 68-69.)
According to both parties' experts, lyophilizing (or freeze-drying) is one of the "top two"
choices a formulator would consider. Tr. 819-20 (Anderson); Tr. 97-98 (Repta). After ProScript
ran into issues developing a liquid formulation that would provide the long-term shelf life needed
for commercialization, Proscript partnered with the National Cancer Institute ("NCI") to develop
a formulation. Tr. 614 (Adams). NCI, in turn, worked with contract formulators at the University
of Kansas ("KU") including Dr. Stella and his assistant Wanda Waugh. Dr. Stella testified that he
initially attempted a liquid formulation. Tr. 457, 510-11 (Stella). Dr. Stella's solution work was
not immediately successful. Tr. 513 (Stella).
He next attempted a freeze-dried formulation
because as he explained "[h]e would be remiss if [he] didn't try [freeze-drying]" after
encountering stability problems with a solution. Tr. 511 (Stella).
The defendants' expert, Dr. Repta, testified to three primary references that establish
lyophilization as a standard formulation option. Tr. 129-31. Tr. 114-17 (Repta); DTX-207-011
(Repta 1981); DTX-728-045 (Phann. Dosage Forms 1992); DTX-556-004 (Remington's 1990).
While a liquid formulation is preferable to a lyophilized formulation, the prior art clearly
established that lyophilized formulations were considered a viable second choice. (See DTX-556004 "[d]espite both the high initial capital equipment costs and the high running costs of the
method, lyophilization has become the most important method for the stabilization of labile
pharmaceutical products with limited shelf lives in dilute solution."). The court agrees that one
skilled in the art would have considered these references in attempting to stabilize bortezomib.
Millennium asserts that "lyophilization would not necessarily address the instability of
bortezomib" because bortezomib was known to be unstable even in the dry state as a freestanding
solid compound. (D.1. 132,
if 77.) Millennium's expert witness, Dr. Anderson, relied on the
Snyder reference to support his opinion that lyophilization may not improve stability of a boronic
acid compound. Tr. 750-51. On cross-examination, however, Dr. Anderson conceded that the
Adams patent discloses the use of lyophilization in a number of examples. Tr. 818-19. Further,
Dr. Anderson agreed that a formulator working with investigational anti-cancer drugs seeking to
develop an intravenous formulation would look to either a ready-to-use liquid solution or freezedrying. Id
The court finds that the testimony of Dr. Repta is persuasive and supported by the
evidence. As of the priority date lyophilization was well-known in the field of formulation and
often utilized when a liquid formulation provided limited success. 9 Dr. Repta credibly testified
and the prior art establishes that lyophilization had been used for decades, and a POSA at least
would have considered the technique in developing stable formulations. Dr. Anderson's expert
opinion did not disprove the defendants' position that freeze-drying was considered by those
skilled in the art to reliably improve stability by eliminating the three main sources of instability
in solutions: molecule movement, hydrolysis, and oxidation. Once a liquid formulation proved
unsuccessful; the obvious next step was to attempt lyophilization. As Dr. Stella noted as early as
1992, "[i]f a drug is unstable in aqueous solution, generally a freeze-dried formulation must be
developed." Tr. 512 (Stella); DTX-742-005 (1992 Stella Ltr.). The court concludes that the
decision to attempt a lyophilized formulation of bortezomib was "[t]he routine application of a
This determination is supported by the positions Millennium took during the inventorship suit and
arbitration against Dr. Stella and his assistant Wanda Waugh. Specifically, Millennium and NCI argued that there
"was nothing inventive about thinking to lyophilize bortezomib." DTX-78-038 (Mill. Arb. Br.). Millennium and
NCI said it was "an expected step under the NCI contract, and it required the exercise of only ordinary skill in the
art," and it was "not a significant or inventive contribution." DTX-261-041-42 (2012 Mill. Arb. Br.). They further
argued that "[a]ll of [Dr. Stella and Ms. Waugh]'s alleged contributions can be dismissed on the ground that they
constituted no more than routine steps based on the exercise of routine skill; indeed, they were natural and expected
formulation options under the contract." DTX-78-038 (Mill. Arb. Br.). Although inventorship and obviousness
inquiries are not identical, Millennium's prior statements appear to confirm that lyophilization was a known and
common technique in the field.
well-known problem-solving strategy" and that of "a skilled artisan, not of an inventor." See
Pfizer, 480 F.3d at 1368 (internal citations omitted).
Decision to Lyophilize Bortezomib with Mannitol was not
Dr. B. Rao Vishnuvajjala from the NCI first "suggested usmg mannitol" to his
subordinate, inventor Dr. Shanker Gupta. Tr. 81-82 (Vishnuvajjala). He made that suggestion
because he "expected that lyophilizing [bortezomib] with mannitol would solve the degradation
issue" and thus "address the stability issue" with the formulation. Tr. 82 (Vishnuvajjala). On
October 6, 1997, Dr. Gupta sent an email to Dr. Stella suggesting four bulking agents for freezedrying, including mannitol, as an "added insurance" policy if the solution work was not
successful. DTX-17-001 (1997 Gupta Email). Far from suggesting that he was offering anything
inventive, Dr. Gupta simply provided a "disparate list of bulking agents" (id), which he expected
to work based on "[his] experience and knowledge oflyophilization." Tr. 318. The KU scientists
started their work on a freeze-dried formulation in "late November" of 1997 (Tr. 516 (Stella)),
and succeeded within weeks, with "the first batch [they] made" with mannitol.
(Stella); PTX-37 at 9 (Dec. 1997 Report). Dr. Stella conceded at trial that Mannitol was an
"obvious option" as the "most popular" bulking agent, and simply "not innovative" to "suggest
using mannitol to freeze-dry bortezomib." Tr. 516, 518, 522-23.
Even Dr. Anderson conceded that a skilled formulator would immediately "consider"
using mannitol (Tr. 800), which was "highly popular." Tr. 848--49. Dr. Repta explained that it
was so popular because "you [can] administer it by intravenous route"; it also "has no
pharmacological effects," is "very water-soluble," and "forms really nice cakes" that "dissolve
rapidly and ... are robust." Tr. 147, 313; see also DTX-738-003 (1994 Handbook); DTX-205001 (Kim 1998); DTX-529-075 (Bashir 1973). He could not "remember using ... anything other
than mannitol as a bulking agent m the numerous formulations [KU] made through
lyophilization." Tr. 146--47.
The Adams patent also pointed directly to mannitol. It taught that freeze-drying was
appropriate for the claimed acids and esters, by including four different freeze-drying examples.
'454 patent at Examples 3.B, 4.B, 8.D, 13.K; Tr. 815-16 (Anderson).
acknowledged nothing in the patent taught "that bortezomib would be any less appropriate for
lyophilization" than compounds in the examples. Tr. 817. The Adams patent explained that
scientists should make esters using "preferably, a dihydroxy compound." Tr. 807 (Anderson); see
'454 patent at 10:12-16. Mannitol is a dihydroxy compound. Tr. 161 (Repta); Tr. 321 (Gupta);
Tr. 508 (Stella); Tr. 600 (Adams); Tr. 672 (Snow); Tr. 807 (Anderson). Dr. Anderson argued that
there are "millions" of "dihydroxy compounds" capable of forming bortezomib esters. Tr. 744,
807-08. 10 But Dr. Repta's explanation that only "half a dozen or so" are "pharmaceutically
acceptable bulking agents" -- the "most prominent" of which is "mannitol" -- is highly
convincing. Tr. 164.
The court concludes that mannitol was among the "finite number of identified, predictable
solutions" to freeze-drying investigational anti-cancer drugs like bortezomib. KSR, 550 U.S. 421.
It was a "suitable option from which the prior art did not teach away." See Par, 2014 WL
6782649, at *9. The choice was an obvious one. In reviewing the prior art, the court finds that
one skilled in the art would have found it obvious to choose mannitol and would have had a
reasonable probability of success in light of the prior art. 11
Dr. Anderson's opinion here is similar to an analogous opinion he offered in Pfizer, where he argued that
there were an "unlimited" number of salt options when in fact there were only 53 FDA approved salts-an opinion
the Federal Circuit said "a reasonable fact-finder could not accept" in view of the FDA limitations imposed on
pharmaceutical products. 480 F.3d at 1362.
11 Again, the court finds the earlier positions of the now named inventors persuasive support for the
proposition that lyophilizing with mannitol was an obvious formulation decision to a POSA. See supra note 8.
Specifically, KU-whi~h gets royalties under the '446 patent-acknowledged that choosing mannitol to freeze-dry
It Would Have Been Obvious to a POSA that Freeze-Drying
Bortezomib with Mannitol Would Produce A BortezomibMannitol Ester
Millennium asserts that even if a POSA were inclined to experiment with lyophilization to
form an ester, "they would understand that formation of the ester would not be inevitable, and
could vary widely depending on the particular conditions used, including concentration, ratios of
ingredients, and temperature." (D.I. 132,
if 90.) Further, Millennium asserts that none of the
references cited by Dr. Repta concerning boron compounds teaches the use of boronate esters to
improve the stability of a boronic acid compound by preventing oxidation.
Millennium points out that the references cited by Dr. Repta teach not only that boron compounds
may form new compounds with dihydroxy compounds under the right conditions but also that the
properties of these compounds are unpredictable. (Id,
iii! 63-64.) Millennium argues that a
POSA formulating bortezomib would avoid forming an ester because the prior art makes clear
that the rate and extent of ester formulation and dissociation is unpredictable. (Id)
The defendants contend that if the court finds obvious the first two steps-freeze-drying
bortezomib with mannitol-the patent is necessarily invalid because ester formation is the
inherent result of that combination. "[I]nherency may supply a missing claim limitation in an
Par, 2014 WL 6782649, at *6.
An element is inherent "when the
limitation at issue is the 'natural result' of the combination of prior art elements." Id at *7. Dr.
Repta explained, mixing bortezomib and mannitol will "inevitabl[y]" form the ester.
bortezomib was obvious: "the idea to try mannitol was natural and expected of those of ordinary skill in the art."
DTX-255-067 (KU Arb. Br.). In 2010, in preparation for a deposition in the royalty dispute, Dr. Adams conducted an
"investigation" about whether Dr. Stella had made an "inventive contribution." Tr. 591 (Adams). Based on that
investigation, Dr. Adams "concluded that [he] had no facts, no evidence, that Dr. Stella had made an inventive
contribution." Tr. 591-92 (Adams). He came to this conclusion even though he knew that Dr. Stella had "freezedried bortezomib with mannitol" and "that procedure produced a bortezomib-mannitol ester." Tr. 591-93 (Adams).
Similarly, seven days before Millennium filed its priority application, Millennium's lead formulator called
the claimed freeze-dried formulation an "obvious option" while noting that "one of the most commonly used
excipients for a lyophilized formula is mannitol." DTX-144-001 (2001 Lai Email); see Tr. 348-50 (McCubbin).
The defendants also assert that Millennium admitted inherency by excluding Dr. Adams as
an inventor even though he was the first to identify the ester formation in October 1998 and
asserting an invention date in December 1997 when Dr. Stella made the claimed formulation.
(D.I. 133, 148.)
The defendants point to Dr. Anderson's acknowledgment that the named
inventors "didn't have any idea that bortezomib had formed an ester with mannitol" before Dr.
Adams' realization, and "there is no evidence that they had the invention in mind" before
September 1998. Tr. 865. Similarly, Dr. Gupta "did not know at that point in time whether an
ester had been formed .... " Tr. 320. Millennium's 30(b)(6) witness, Dr. Quentin McCubbin,
affirmed "it wasn't Dr. Gupta who had the idea ... that [they] were forming an ester"; "[t]here's
no evidence that [Dr. Stella] had thought about an ester formation"; and Ms. Waugh "didn't know
anything about the ester." Tr. 342. In fact, Dr. Stella admitted that he "didn't learn that the ester
had formed" until "around 2005," "when [he] read the ['446] patent."
defendants argue that by omitting Dr. Adams from its patent application and claiming an
invention date of December 1997, Millennium conceded as a matter of law that the ester is the
"natural result" of freeze-drying bortezomib with mannitol. (D.I. 132,
if 150 (quoting Par, 2014
WL 6782649, at *7). The court agrees and concludes that the inventors were not required to
recognize the ester as of December 1997 because it is an "inherent propert[y]" that falls under the
"rare exception to the rule" that "every limitation" of a claim "must have been known to the
inventor at the time of the alleged conception." Hitzeman v. Rutter, 243 F.3d 1345, 1354-55
(Fed. Cir. 2001).
The Adams Patent Provided a POSA the Motivation to Combine
Millennium cannot claim that the prior art teaches against what its own prior art patent
affirmatively claims. Millennium's patent-the Adams patent-specifically teaches that
formulators "can use" the claimed "esters as pharmaceutical compositions." Tr. 607:13-16
The patent also specifically claims "pharmaceutical compositions" of bortezomib
"esters" to be used as "prodrugs," including the mannitol ester. '454 patent 65:19-21, 66:28-30;
Tr. 870, 874, 875-77, 880 (Anderson).
Second, as Dr. Repta explained, skilled formulators
would be motivated to create a mannitol ester to improve bortezomib's stability and solubility.
Tr. 169. Millennium's 30(b)(6) witness agreed, saying that the "first thing to do to stabilize
[boronic acids like bortezomib] would be to form an ester." Tr. 335 (McCubbin). And while he
emphasized there were no guarantees, Dr. Anderson similarly conceded that "ester formation can
dramatically increase the solubility of a compound," "especially" when the ester is formed with a
"highly soluble" "molecule like mannitol." Tr. 847. Third, as Dr. Anderson conceded, ester
formation is "generally" "not a problem" because when you "put an ester in water ... you expect
it to hydrolyze" (Tr. 836), meaning the ester breaks apart, thus freeing the active ingredient to
achieve its biological activity in the body. Tr. 867. Dr. Repta shared this view (Tr. 152-53, 30405), as did Dr. McCubbin. Tr. 350-51. That is precisely what the Adams patent claimed and
taught happens with the claimed esters. Tr. 870-73 (Anderson). For the reasons stated above, the
court concludes that the defendants have established a prima facie case that the '446 patent was
obvious in light of the prior art.
4. Secondary Considerations
The final factor in assessing obviousness is evaluating the objective indicia of nonobviousness, often referred to as secondary considerations. Millennium argues that the relevant
considerations in this case are unexpected results, commercial success, and long-felt but unmet
"Although secondary considerations must be taken into account, they do not necessarily
control the obviousness conclusion." Pfizer, 480 F.3d at 1372. A strong case of prima facie
obviousness . .
cannot be overcome by a far weaker showing of objective indicia of
Takai Corp. v. Easton Enters., Inc., 632 F.3d 1358, 1371.
"[a] nexus between the merits of the claimed invention and evidence of secondary considerations
is required in order for the evidence to be given substantial weight in an obviousness decision."
Muniauction, Inc. v. Thomson Corp., 532 F.3d 1318, 1327 (Fed. Cir. 2008) (alteration in original)
(quoting Ruiz v. A.B. Chance Co., 234 F.3d 654, 668 (Fed. Cir. 2000)). In other words, the
secondary considerations must be commensurate in scope-"coextensive"-with the claimed
features of the invention. Id; see also MeadWestVaco Corp. v. Rexam Beauty & Closures, Inc.,
731F.3d1258, 1264-65 (Fed. Cir. 2013).
Millennium asserts that a person of ordinary skill would not have expected a lyophilized
mannitol ester of bortezomib to provide these dramatic improvements in stability, solubility and
dissolution as compared to bortezomib. (D.I. 132,
100.) Millennium failed to present any
credible evidence at trial about what a skilled artisan would have expected. See Bristol-Myers,
752 F.3d at 977 ("[E]vidence of unexpected results must establish ... that the difference would
not have been expected by one of ordinary skill in the art at the time of the invention.").
Millennium's experts testified that they did not know whether the bortezomib-mannitol ester was
more stable or soluble than the closest prior art bortezomib glycerol ester. Tr. 890-91 (Anderson);
Tr. 684 (Snow). Millennium also failed to establish any difference between the claimed invention
and the closest prior art. See Bristol Myers, 752 F.3d at 977 ("[E]vidence of unexpected results
must establish that there is a difference between the results obtained [through the claimed
invention] and those of the closest prior art[.]"). Millennium's experts compared the bortezomib-
mannitol ester to examples that did not contain esters. The court agrees with the defendants that
the closest prior art were the bortezomib esters disclosed in the Adams patent.
Commercial Success and Long-Felt Need
Commercial success is an indication of nonobviousness "because the law presumes an
idea would successfully have been brought to market sooner, in response to market forces, had the
idea been obvious to persons skilled in the art." Merck & Co., Inc. v. Teva Pharm. USA, Inc., 395
F.3d 1364, 1376 (Fed. Cir. 2005). When commercial success has been demonstrated and "the
successful product is the invention disclosed and claimed in the patent, it is presumed that the
commercial success is due to the patented invention." J. T Eaton & Co. v. At!. Paste & Glue Co,
106 F.3d 1563, 1571 (Fed. Cir. 1997); see also Demaco Corp. v. F Von Langsdorff Licensing
Ltd., 851 F.2d 1387, 1394 (Fed. Cir. 1988) ("It is sufficient to show that the commercial success
was of the patented invention itself.").
Millennium's commercial success and long-felt need arguments focus on the fact that
"[t]he bortezomib compound alone cannot be administered to patients, and therefore required a
pharmaceutical formulation." (D.I. 132,
if 35.) Here, the Adams patent precluded alternative
inventions from competing in the market. The evidence at trial established that a number of other
formulations provided a viable route to commercial production but were disregarded on economic
rather than efficacy grounds. No persuasive evidence was provided to show any advantage
attributable to the claimed formulation over the other potential formulations available to
For substantially the same reasons, Millennium was similarly unsuccessful m
presenting persuasive evidence of a long-felt need. While the success of bortezomib in treating
multiple myeloma cannot be understated, 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
.... " Hitachi Koki Co. v. Doll, 620 F. Supp. 2d 4, 30 (D.D.C. 2009).
Based on the evidence presented at trial, the court concludes that Millennium's assertions
do not undermine its obviousness finding.
In sum, the defendants have presented a prima facie case by clear and convmcmg
evidence that the asserted claims of the patents-in-suit are invalid as obvious. Moreover, the court
finds that the secondary, objective indicia do not overcome the finding of obviousness. The
defendants have shown by clear and convincing evidence that the '446 patent is obvious and
therefore invalid under 35 U.S.C. § 103.
For the reasons stated above, the court concludes that: (1) the asserted claims of the '446
are invalid due to obviousness. (2) The defendants' Rule 52(c) motion (D.I. 133) is granted. (3)
Millennium's Rule 52(c) motion (D.I. 132) is denied.
1\-, _;; /)_ 'J4 ,
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