Vifor Fresenius Medical Care Renal Pharma Ltd. et al v. Lupin Atlantis Holdings SA et al
Filing
325
MEMORANDUM OPINION. Signed by Judge Maryellen Noreika on 8/18/2022. (dlw)
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 1 of 58 PageID #: 8154
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
VIFOR FRESENIUS MEDICAL CARE
RENAL PHARMA LTD. and VIFOR
FRESENIUS MEDICAL CARE RENAL
PHARMA FRANCE S.A.S.,
Plaintiffs
v.
TEVA PHARMACEUTICALS USA, INC.,
Defendant.
)
)
)
)
)
)
)
)
)
)
)
)
C.A. No. 18-390 (MN)
MEMORANDUM OPINION
Brian E. Farnan, Michael J. Farnan, FARNAN LLP, Wilmington, DE; Raymond N. Nimrod,
Matthew A. Traupman, Geoffrey A. Kirsner, QUINN EMANUEL URQUHART & SULLIVAN, LLP,
New York, NY; Steven C. Cherny, Lauren N. Martin, QUINN EMANUEL URQUHART & SULLIVAN,
LLP, Boston, MA, Nancy Zhang, QUINN EMANUEL URQUHART & SULLIVAN, LLP, San Francisco,
CA – Attorneys for Plaintiffs
John W. Shaw, Karen E. Keller, Nathan R. Hoeschen, SHAW KELLER LLP, Wilmington, DE; Scott
J. Bornstein, Richard C. Pettus, Jonathan D. Ball, GREENBERG TRAURIG, LLP, New York, NY;
Jonathan R. Wise, GREENBERG TRAURIG LLP, Philadelphia, PA – Attorneys for Defendant
August 18, 2022
Wilmington, Delaware
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 2 of 58 PageID #: 8155
NOREIKA, U.S. DISTRICT JUDGE:
Plaintiffs Vifor Fresenius Medical Care Renal Pharma Ltd (“Vifor Switzerland”) and Vifor
Fresenius Medical Care Renal Pharma France S.A.S. (“Vifor France”) (collectively “Plaintiffs” or
“Vifor”) brought this Hatch-Waxman action against Defendant Teva Pharmaceuticals USA, Inc.
(“Defendant” or “Teva”). Teva has filed an Abbreviated New Drug Application (“ANDA”) with
the U.S. Food and Drug Administration (“FDA”) seeking approval to market a generic version
(“ANDA product”) of Vifor’s Velphoro® product before expiration of United States Patent No.
9,561,251 (JTX-1 (“the ’251 patent”)). Plaintiffs allege that Teva’s ANDA product will infringe
claims 29, 30, 33, and 56 of the ’251 patent. Teva denies infringement of claims 29 and 30 and
asserts that all four of the asserted claims are invalid.
The Court construed the disputed claim terms on September 5, 2019. (D.I. 114). 1 In
January 2021, the Court conducted a four-day bench trial. (See D.I. 302-305 (“Tr.”)). The parties
completed post-trial briefing on April 7, 2021. (D.I. 297, 299, 307, 309, 312, 313). With their
briefing, the parties submitted proposed findings of fact. (D.I. 298, 300, 306, 308).
Pursuant to Rule 52(a) of the Federal Rules of Civil Procedure, and after having considered
the entire record and the applicable law, the Court concludes that: (1) Teva’s ANDA product
infringes claims 33 and 56 of the ’251 patent; 2 (2) Vifor has proved that Teva’s ANDA product
infringes claims 29 and 30 of the ’251 patent; (3) Teva has failed to prove that claims 29, 30, 33,
and 56 of the ’251 patent are invalid for obviousness; and (4) Teva has failed to prove that claims
1
This case was originally assigned to the Honorable Leonard P. Stark and reassigned to the
undersigned judge on December 12, 2019. Judge Stark construed the disputed claim terms.
2
Defendant stipulated to infringement of claims 33 and 56 if those claims are valid.
1
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 3 of 58 PageID #: 8156
29 and 30 are invalid for lack of enablement. This opinion constitutes the Court’s findings of fact
and conclusions of law.
I.
FINDINGS OF FACT (“FF”)
A.
Introduction
1.
Plaintiff Vifor Switzerland is a corporation organized and existing under the laws
of Switzerland and has its principal place of business at Rechenstraße 37, St. Gallen, 9011,
Switzerland. (D.I. 277, Ex. 1 ¶ 2).
2.
Plaintiff Vifor France is a simplified joint stock company (société par actions
simplifiée) organized and existing under the laws of France and has its principal place of business
at 100-101 Terrasse Boieldieu Tour Franklin La Défense 8 F-92042 Paris La Défense Cedex,
France. Vifor France is a wholly-owned subsidiary of Vifor Switzerland. (Id. at Ex. 1 ¶ 3).
3.
Defendant Teva is a corporation organized and existing under the laws of the State
of Delaware and has its principal place of business at 1090 Horsham Road, North Wales,
Pennsylvania 19454. (Id. at Ex. 1 ¶ 5).
4.
This case concerns the ’251 patent, which is listed in the FDA publication,
“Approved Drug Products with Therapeutic Equivalence Evaluations” (“the Orange Book”), as
having at least one claim that covers Velphoro. (D.I. 277, Ex. 1 ¶ 11).
5.
Teva submitted ANDA No. 211411 (“Teva’s ANDA”) to the FDA on
November 27, 2017 seeking approval to engage in the commercial manufacture, use, offer for sale
and/or sale of its ANDA product, i.e., sucroferric oxyhydroxide chewable tablets, 500 mg.
(D.I. 277, Ex. 1 ¶ 14).
Teva’s ANDA contains a certification under 21 U.S.C.
§ 355(j)(2)(A)(vii)(IV) that states that the ’251 patent is “invalid, unenforceable, and/or will not
2
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 4 of 58 PageID #: 8157
be infringed by the commercial manufacture, use or sale” of the ANDA product. (D.I. 277, Ex. 1
¶ 15).
B.
Witnesses
1.
6.
Fact Witnesses
Hemant Mamania testified by deposition. Dr. Mamania is a senior director and site
head for the Ambernath solid oral site of Watson Pharma. 3 (Tr. at 59:2-7).
7.
Parven Luthra testified by deposition. Dr. Luthra is senior director, R&D in India
for Teva. (Tr. at 70:17-22).
8.
Erik Philipp testified by deposition. Dr. Philip is the head of chemical and
analytical development for Vifor (Tr. at 228:25-229:9) and a named inventor on the ’251 patent
(JTX-1).
9.
Laurent Chofflon testified by deposition.
Mr. Chofflon works in external
development for chemistry, manufacturing, and control for Vifor. (Tr. at 268:3-15).
2.
10.
Plaintiffs’ Expert Witnesses
Anjay Rastogi testified live at trial. 4 Dr. Rastogi is Chief of Nephrology at UCLA
Health in the Department of Medicine, Division of Nephrology. (Tr. at 77:11-20). He has a
medical degree and a Ph.D. in pharmacology. (PTX-555). Dr. Rastogi was the principal
investigator at UCLA, one of the major sites for the Velphoro Phase III clinical studies. (Tr. at
86:17-87:16). He was also a member of the Velphoro Steering Committee. (Id.). The Court
recognized Dr. Rastogi as an expert in pharmacology, nephrology, and the treatment of
hyperphosphatemia. (Tr. at 88:10-22).
3
Watson Pharma is “a part of the Teva company.” (Tr. at 58:22-59:1).
4
The Court found Dr. Rastogi to be a particularly credible witness.
3
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 5 of 58 PageID #: 8158
11.
Adam Myers testified live at trial. Dr. Myers is a senior project manager at Evonik
Corporation and president of Coldbrook Consulting. (Tr. at 142:11-14). Dr. Meyers has a Ph.D.
in organic chemistry. (PTX-603). He has expertise in evaluation of drug performance, including
various types of testing. (PTX-603; Tr. at 143:3-10). The Court recognized Dr. Myers as an expert
in testing and analysis of pharmaceutical products, including dissolution testing and analysis.
(Tr. at 144:5-12).
12.
Carla Mulhern testified live at trial. Ms. Mulhern received a bachelor’s degree in
mathematics from Bucknell University and a master’s degree in economics from the London
School of Economics. (Tr. at 562:14-18; DTX-313A). She is a managing principal at Analysis
Group, an economic and financial consulting firm. (Tr. at 561:22-562:13). Ms. Mulhern has
opined on commercial success in patent infringement cases on behalf of both patent holders and
alleged infringers across a variety of products and industries, including pharmaceuticals, medical
devices, semiconductors, and consumer electronics equipment. (Tr. at 563:13-564:5). The Court
recognized Ms. Mulhern as an expert in economics. (Tr. at 564:6-11).
13.
Robert O. Williams III testified live at trial. Dr. Williams is a professor of
pharmacy at the University of Texas Austin College of Pharmacy. (Tr. at 644:4-19; DTX-280).
He received bachelor’s degrees in biology and pharmacy from Texas A&M and the University of
Texas at Austin, respectively. (Id.). He also received a Ph.D. in Pharmaceutics from the University
of Texas at Austin. (Id.). Prior to entering academia, Dr. Williams worked for about ten years
developing dry products, including solid oral dosage forms such as suspensions. (Tr. at 644:2045:6). The Court recognized Dr. Williams as an expert in the design and development of
pharmaceutical formulations. (Tr. at 645:15-22).
4
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 6 of 58 PageID #: 8159
3.
14.
Defendant’s Expert Witnesses
Stephen Z. Fadem testified live at trial. Dr. Fadem has a medical degree from the
University of Oklahoma College of Medicine. (Tr. at 208:2-9). He is a practicing physician and
a clinical professor at Baylor College of Medicine. (Tr. at 207:9-16). He also teaches at the
DeBakey Veterans Administration Hospital in Houston, Texas. (Tr. at 207:17-19). He has been
practicing nephrology and treating patients with chronic kidney disease for more than forty years.
(Tr. at 207:20-208:1). The Court recognized Dr. Fadem as an expert in the diagnosis and treatment
of patients that have chronic kidney disease, including patients who are on dialysis. (Tr. at 210:21211:3).
15.
Walter G. Chambliss testified live at trial. Dr. Chambliss is a professor emeritus of
pharmaceutics and drug delivery and a research professor emeritus in the Research Institute of
Pharmaceutical Sciences at the University of Mississippi.
(Tr. at 278:2-24; DTX-1060).
Dr. Chambliss received a bachelor’s degree in Pharmacy, as well as a master’s degree and Ph.D.
(both in Pharmaceutics) from the University of Mississippi. (Tr. at 279:21-280:2). He has more
than forty years of experience in research for pharmaceutical formulations, including phosphate
binders, as well as experience in pharmaceutical development. (Tr. at 278:2-285:2; DTX-1060).
The Court recognized Dr. Chambliss as an expert in pharmaceutical science and formulation.
(Tr. at 285:10-16).
16.
Robert DeForest McDuff testified live at trial. Dr. McDuff is an economics
consultant at Insight Economics, a consulting firm that he co-founded in 2017. (Tr. at 742:1643:4; DTX-148A). He received a bachelor’s degree in economics and mathematics from the
University of Maryland and a master’s degree and a Ph.D. in economics from Princeton University.
(Id.). He has worked on more than fifty cases evaluating pharmaceuticals and the issue of
5
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 7 of 58 PageID #: 8160
commercial success and has published several articles on the topic of commercial success. (Id.).
The Court recognized Dr. McDuff as an expert in economics and commercial success. (Tr. at
743:5-10).
C.
The ’251 Patent
17.
The
’251
patent,
entitled
Pharmaceutical
Compositions,
issued
on
February 7, 2017. (JTX-1). The ’251 patent claims priority to PCT/EP2008/065444 filed on
November 13, 2008, which in turn claims priority to EP 07120837 filed on November 16, 2007.
(D.I. 277, Ex. 1 ¶ 8). The § 371 date is May 14, 2010. (JTX-1).
18.
The inventors of the ’251 patent are Ludwig Daniel Weibel and Erik Philipp.
(D.I. 277, Ex. 1 ¶ 7).
19.
The ’251 patent is directed to pharmaceutical compositions with a high load of iron
oxy-hydroxide – at least 500 mg iron oxy-hydroxide per dosage form – in a form suitable for oral
administration. (E.g., JTX-1 at 1:5-11, 15:23-31).
20.
Vifor Switzerland is the current owner of the ’251 patent. (D.I. 284).
21.
Vifor asserts claims 29, 30, 33, and 56 against Teva. Claims 29, 30, and 33 are
dependent on Claim 1, which claims:
A pharmaceutical composition comprising an effective phosphateadsorbing amount of iron oxy-hydroxide in high loading of 10 to
80% (w/w) expressed in relation to the total weight of the
pharmaceutical composition, and carbohydrates, said carbohydrates
compromising saccharose and starch, in a form suitable for oral
administration, wherein the amount of iron oxy-hydroxide per
dosage form is at least 500 mg.
22.
Claim 29 adds:
The composition according to claim 1, wherein the iron oxyhydroxide is essentially non-bioabsorbable.
6
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 8 of 58 PageID #: 8161
23.
Claim 30 adds to claim 1:
The composition according to claim 1, having an iron release rate of
below 2.5% w/w.
24.
Dependent claim 33 claims:
The composition according to claim 32, wherein dosage form is
selected from chewable tablets.
25.
Claim 32, in turn, claims:
The composition according to claim 1, which is a dosage form
capable of disintegration in the oral cavity.
26.
Dependent claim 56 depends from dependent claim 55, which depends from
independent claim 27. Claim 27 claims:
A method for treating hyperphosphatemia, comprising the steps of
orally administering a pharmaceutical composition comprising an
effective phosphate-adsorbing amount of iron oxy-hydroxide in
high loading of 10 to 80% (w/w) expressed in relation to the total
weight of the pharmaceutical composition, and carbohydrates, said
carbohydrates comprising saccharose and starch, in a form suitable
for oral administration, wherein the amount of iron oxy-hydroxide
per dosage form is at least 500 mg to a patient in need thereof.
27.
Claim 55 claims:
The method according to claim 27, comprising 700 to 1700 mg iron
oxy-hydroxide per dosage form.
28.
Claim 56 claims:
The method according to claim 55, comprising about 800 mg iron
oxy-hydroxide per dosage form.
D.
Velphoro
29.
Vifor France holds an approved New Drug Application (“NDA”) under Section
505(a) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 355(a), for sucroferric
7
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 9 of 58 PageID #: 8162
oxyhydroxide chewable tablets, 500 mg (NDA No. 205109), sold under the trade name Velphoro.
Vifor France received FDA approval for Velphoro in November 2013. (D.I. 277, Ex. 1 ¶ 10).
30.
Velphoro is “a phosphate binder indicated for the control of serum phosphorus
levels in patients with chronic kidney disease on dialysis.” (DTX-264 at 2).
31.
Patients with chronic kidney disease may suffer from hyperphosphatemia, which
means their serum phosphorus levels are above the normal acceptable range for the general
population. (Tr. at 84:10-14). Hyperphosphatemia can cause calcification in the blood vessels
and some other tissues resulting in decreased elasticity. (Tr. at 84:15-85:2).
32.
Velphoro contains iron oxy-hydroxide, sucrose (saccharose), and starch. (DTX-
264 at 6).
Each 2577.5 mg chewable Velphoro tablet 5 contains 2500 mg of sucroferric
oxyhydroxide, which corresponds to 500 mg of iron, which in turn corresponds to 800 mg of iron
oxy-hydroxide. (PTX-322 at 10; Tr. at 698:19-699:2). Thus, iron oxy-hydroxide equals 31.0
percent by weight of the Velphoro tablet. (Tr. at 699:6-11).
33.
The active moiety of Velphoro, polynuclear iron(III)-oxyhydroxide (pn-FeOOH),
is practically insoluble and therefore not absorbed and not metabolized. (DTX-264 at 6).
34.
Velphoro satisfies all of the limitations of the four asserted claims and is an
embodiment of those claims. (Tr. at 698:16-700:12; PTX-322 at 57; DTX-264 at 6). 6
E.
Person of Skill in the Art
35.
Plaintiffs’ expert opined that a “person of ordinary skill in the art [“POSA”] would
have at least the equivalent of a master’s degree in chemistry, chemical engineering, pharmacy,
5
A chewable tablet is a dosage form capable of disintegration in the oral cavity. (JTX-1,
col. 3, l. 52-67).
6
Teva does not dispute that Velphoro practices all of the limitations of the four asserted
claims.
8
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 10 of 58 PageID #: 8163
pharmacology or pharmaceutics or a comparable field, and four years of academic research or
industry experience related to pharmaceutical formulation development. Alternatively, the POSA
can have a higher level of formal education such as a Ph.D. and with subsequent fewer years of
relevant experience. The POSA would also have access to individuals with knowledge and
experience in fields such as iron chemistry, iron biochemistry, nephrology and treatment of
patients with chronic kidney disease.” (Tr. at 646:3-16).
36.
According to Defendant, a POSA at the relevant time would have possessed at least
a bachelor’s degree, and more likely a master’s or Doctoral degree, in the field of pharmaceutical
sciences or a related discipline, and several years of experience formulating dosage forms
containing pharmaceutically active compounds. A POSA could have a lower level of formal
education if such person had a higher degree of experience. Furthermore, because drug discovery
and development is a multidisciplinary effort, a POSA might interface or consult with individuals
having specialized expertise such as, for example, a physician with experience in the
administration, dosing, and efficacy of drugs for treating hyperphosphatemia. (D.I. 300 ¶ 22).
37.
There is no meaningful difference between the parties’ proposed definitions. Each
of the experts who opined on the definition of a person of skill in the art agreed that his opinions
would not change regardless of what definition of a POSA were used. (Tr. at 216:20-22 (Fadem);
Tr. at 287:7-14 (Chambliss); 645:24-647:1 (Williams)).
38.
Dr. Rastogi (PTX-555), Dr. Myers (Tr. at 142:24-144:4), 7 Dr. Fadem (Tr. at 216:2-
19), Dr. Chambliss (Tr. at 287:15-17), and Dr. Williams (Tr. at 644:4-19, 645:24-646:18) meet the
definitions of a POSA offered by both sides.
7
Teva asserts that Plaintiffs made no “showing or attempt to qualify Dr. Myers” as a POSA
at trial. (D.I. 309 at 8, n.8). The evidence shows that Dr. Myers has a Ph.D. in organic
chemistry and more than ten years of experience in analyzing pharmaceutical formulations.
9
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 11 of 58 PageID #: 8164
F.
Facts Relevant to Infringement
1.
39.
Teva’s ANDA Product 8
Teva’s sucroferric oxyhydroxide ANDA product is a phosphate binder indicated
for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.
(DTX-152 at 2). The package insert instructs healthcare professionals to administer Teva’s ANDA
product as a phosphate binder to control serum phosphorus levels in patients with chronic kidney
disease on dialysis (i.e., hyperphosphatemia). (DTX-152 at 2).
40.
Teva’s ANDA product is a chewable tablet, which is a dosage form capable of
disintegration in the oral cavity in the form of a chewable tablet. (D.I. 277, Ex. 1 ¶¶ 20-21; DTX152 at 1, 5).
41.
Teva represented to the FDA that its ANDA product “is deemed therapeutically
equivalent to Velphoro®.” (DTX-171 at 28; Tr. at 99:4-17). 9 It represented that its ANDA product
contains “the same active ingredients . . . as well as the same route of administration, dosage and
strength” and “was demonstrated to be comparable to Velphoro®.” (DTX-171 at 28; see also PTX7; Tr. at 97:12-23).
(PTX-603). This is consistent with Dr. Myers’ testimony that he is a person of ordinary
skill in the art. (See Tr. 186:15-16).
8
Teva’s ANDA product will be manufactured at Watson Pharma Private Ltd., which is a
part of Teva. (DTX-171 at 66; PTX-7 at 1).
9
The FDA defines “bioequivalence” as “the absence of a significant difference in the rate
and extent to which the active ingredient or active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug action when administered
at the same molar dose under similar conditions in an appropriately designed study.”
21 C.F.R. § 314.3(b).
10
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 12 of 58 PageID #: 8165
42.
Teva submitted an in-vitro bioequivalence equilibrium binding and in-vitro
bioequivalence kinetic binding study in its ANDA for the purpose of showing that its ANDA
product is bioequivalent to Velphoro in phosphate binding capacity. (D.I. 277, Ex. 1 ¶ 17).
43.
Based on its showing of bioequivalence to Velphoro, Teva was able to rely upon
the clinical studies conducted on Velphoro in its submissions to the FDA. (Tr. at 96:17-97:8).
44.
As of the date of this opinion, Teva has not received approval (tentative or final)
for its product. (D.I. 321).
2.
45.
Claims 1, 33, and 56
Teva does not contest that its ANDA product includes each limitation of unasserted
claim 1 of the ’251 patent (from which asserted claims 29, 30, 33, and 56 depend). (D.I. 277,
Ex. 1 ¶ 23).
46.
Teva does not contest that its ANDA product includes the additional limitation of
claim 33 and Teva agrees that Plaintiffs have satisfied their burden of proof with respect to
infringement of claim 33. (D.I. 277, Ex. 1 ¶ 24). 10
47.
Teva does not contest that its ANDA product includes all of the limitations of claim
56 of the ’251 patent and/or indirectly infringes claim 56 of the ’251 patent. Teva agrees that
Plaintiffs have satisfied their burden of proof with respect to infringement of claim 56. (D.I. 277,
Ex. 1 ¶ 25).
3.
48.
Claim 29
The only dispute about infringement of claim 29, which depends on claim 1, is
whether Teva’s ANDA product meets the “essentially non-bioabsorbable” limitation.
10
In the Pretrial Order (D.I. 277, Ex. 1 ¶¶ 24-25), Teva noted that its agreement was “subject
to its non-infringement defense under the reverse doctrine of equivalents.” Teva, however,
later dropped its reverse doctrine of equivalents defense.
11
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 13 of 58 PageID #: 8166
49.
The Court construed “essentially non-bioabsorbable” to mean “upon oral
administration, the iron oxyhydroxide is not absorbed by the human body in a clinically significant
amount.” (D.I. 114 at 5).
50.
Iron is potentially toxic when in the body in high amounts. (Tr. at 104:3-20). There
are two types of iron toxicity. One is potentially fatal acute iron poisoning, which can cause
vomiting, diarrhea, and bleeding. The second is iron overload (hemochromatosis), which can lead
to organ damage, especially the liver. (Id.).
51.
Iron absorption into the body also can also affect phosphate binding capacity and
lower the efficacy of a phosphate binder. (Tr. at 112:1-113:20).
52.
The proposed label for Teva’s ANDA product states: “[s]ince the absorption of iron
from sucroferric oxyhydroxide is low . . . the risk of systemic iron toxicity is low.” (D.I. 277,
Ex. 1 ¶ 22).
53.
Teva’s package insert states that the “active moiety of sucroferric oxyhydroxide,
polynuclear iron (III)-oxyhydroxide (pn-FeOOH), is practically insoluble and therefore not
absorbed and not metabolized” and “[t]he active moiety, polynuclear iron (III)-oxyhydroxide, is
practically insoluble and cannot be absorbed.” (DTX-152 at 5-6).
54.
Teva’s package insert includes a description of an iron uptake study using
radiolabeled sucroferric oxyhydroxide drug substance in 16 chronic kidney disease patients and
8 healthy volunteers.
The only source of radiolabeled iron in the study was sucroferric
oxyhydroxide. (DTX-152 at 6). The study reported that, in chronic kidney disease patients, the
median iron uptake was 0.04% on Day 21, which is considered “quite low and insignificant.”
(Tr. at 103:17-104:2 (discussing DTX-152 at 6)).
12
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 14 of 58 PageID #: 8167
55.
Physicians rely on a drug’s package insert, which contains vital information such
as dosing, drug interactions, and warnings, to determine whether to use a drug to treat patients,
and how to use that drug treat patients. (Tr. at 99:24-100:17, 104:21-105:3). When prescribing
generic drugs, physicians expect that a generic drug behaves in the same manner as the branded
drug. (Tr. at 104:21-105:19).
56.
Although the clinical study of iron uptake referenced in Teva’s package insert was
conducted by Vifor using Velphoro, not the Teva ANDA product (Tr. at 103:6-8), if the data and
statements made regarding the “low and insignificant” iron uptake were untrue as to Teva’s ANDA
product, that would put patient safety in jeopardy (Tr. at 101:13-19).
57.
Teva has not informed the FDA that any statements in the package insert for its
ANDA product may be incorrect or doubtful. Nor has Teva informed the FDA that it does not
know the level of absorption of iron oxy-hydroxide from Teva’s ANDA product or that it requires
additional clinical testing to make that determination.
58.
Additional Teva documents also indicate that the iron oxy-hydroxide in Teva’s
ANDA product is not absorbed in clinically significant amounts.
Teva’s pharmaceutical
development report, submitted as part of its ANDA submission to the FDA, states:
•
the iron oxy-hydroxide in its ANDA product “is not intended to be
absorbed in vivo.” (DTX-172 at 3);
•
a “special” feature of the product is “the fact that [i]ron from the
product is not available in soluble form to be absorbed in the
[gastrointestinal tract].” (DTX-172 at 7);
•
“sucroferric oxyhydroxide tablets are not expected to release free
iron over the GI physiology and their by [sic] avoid possibility of
any adverse effects associated with high intake of iron.” (DTX-172
at 14);
•
that dissolution tests comparing Teva’s ANDA product to Velphoro
showed that “[b]oth test and reference did not show release [of iron]
13
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 15 of 58 PageID #: 8168
in most relevant fed state pH of GI tract” and that the results were
consistent with other literature that “indicate negligible release of
iron in the [gastrointestinal tract] for absorption.” (DTX-172 at 22).
59.
Another Teva product development document describes the “poor solubility and
nonabsorbed nature” of Teva’s ANDA product. (DTX-177 at 4). It also states that “[i]ron from
the product is not available in soluble form to be absorbed in the [gastrointestinal tract].” (DTX177 at 10). That exhibit describes dissolution tests that were conducted comparing Teva’s ANDA
product to Velphoro, which showed that “[b]oth test and reference did not show release in most
relevant fed state pH of GI tract” and that the results were consistent with other literature that
“indicate negligible release of iron in the [gastrointestinal tract] for absorption.” (DTX-177 at 36).
60.
Teva’s corporate representative, Hemant Mamania, confirmed the accuracy of the
statements in the documents. For example, Dr. Mamania confirmed that Teva did not doubt that
the API used in Teva’s ANDA product would not be absorbed from the gastrointestinal tract into
systemic circulation (Tr. at 61:20-25) and that Teva relied upon the knowledge that the API used
in Teva’s ANDA product would not be absorbed from the gastrointestinal tract into systemic
circulation in developing its formulation (Tr. at 62:1-14). Dr. Mamania also testified that he was
aware that free iron absorption can lead to toxicity, and a point of developing Teva’s ANDA
product was to avoid having free iron that can be absorbed. (Tr. at 74:24-75:11).
61.
Teva’s expert, Dr. Fadem, did not address or offer opinions on the statements in
Teva’s pharmaceutical development documents. (Tr. at 222:2-13).
62.
The iron oxy-hydroxide in Teva’s proposed ANDA product is “essentially
nonbioabsorbable” as that term has been construed by the Court. As that is the only disputed
element, Teva’s proposed ANDA product meets each and every element of claim 29.
14
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 16 of 58 PageID #: 8169
4.
63.
Claim 30
As noted above, claim 30 depends on claim 1. The only disputed element regarding
infringement of claim 30 is whether Teva’s ANDA product meets the additional limitation of claim
30, i.e., “having an iron release rate of below 2.5% w/w.”
64.
During claim construction, the Court construed “iron release rate below 2.5% w/w”
to mean “the iron release measured in water at a pH of 3 according to European Pharmacopeia
(“EP”) chapter 2.9.3[11] using standard dissolution equipment and parameters as described in the
monograph, where iron content is analyzed by titration after 2 hours, wherein the quantity of iron
dissolved after 2 hours is less than 2.5% w/w.” 12 (D.I. 114 at 7).
65.
At trial, the parties disputed whether the Court’s construction requires a pH of 3 (as
stated) or a pH of 3.0.
66.
Plaintiffs’ expert, Dr. Myers, was the only witness to testify about infringement of
claim 30. Teva did not offer any expert or fact testimony to rebut Dr. Myers’ testing, methodology
or results or his understanding and application of the Court’s claim construction in his infringement
analysis.
67.
The ’251 patent refers to pH in two places: first, referring to polymer coating,
noting that “[s]uitable polymers . . . are soluble at pH of from about 1.2 to about 5” (JTX-1 at 9:10-
11
EP 2.9.3 provides guidance for instrumentation and test parameters for performing
dissolution testing on a variety of dosage forms. (PTX-246; Tr. at 146:3-9).
12
The ’251 patent describes results for “[iron] release at pH 3,” which was measured
“according to European Pharmacopeia chapter 2.9.3 using standard dissolution equipment
and parameters as described in the monograph. The test medium is water, pH 3 was
adjusted using hydrochloric acid. Samples were analyzed after 2 [hours] and iron content
analyzed by titration.” (JTX-1 at 14:43-53).
15
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 17 of 58 PageID #: 8170
11) and second, discussing iron release testing in Example 8 and Table 9b and referring repeatedly
to pH of 3 (JTX-1 at 14:40-15:20 (including Table 9(b))).
68.
The patentees understood how to specify pH to a decimal place (e.g., 1.2) when
they intended to do so. The patentees did not do so with respect to the pH of 3, instead expressing
it as a whole number.
69.
A POSA would understand that pH 3, expressed as a whole number in the patent,
would mathematically encompass a range of 2.5-3.4 and would understand that, if the patent
required a pH to be more specific than that range, the pH would be identified with additional
decimal places. (Tr. at 162:7-15, 181:23-182:6).
70.
A POSA would further understand that measurement of the iron release at a pH of 3
is intended to simulate the fed state of the stomach, which would exist in a pH range that
encompasses 2.5-3.4, though almost never at a pH of exactly 3.0. (Tr. at 150:6-12, 162:7-15,
164:22-165:2).
71.
Dr. Myers is the only expert who performed iron release testing consistent with the
Court’s construction and the process detailed in the ’251 patent, which requires measurement in
water at a pH of 3 according to EP 2.9.3 using standard dissolution equipment and parameters as
described in the monograph.
72.
Initial testing showed that the disintegration of Teva’s ANDA product tablets
(which occurred before dissolution) 13 caused the pH of the medium to increase from 3 to about 6
before dissolution testing began. (Tr. at 152:10-153:20, 154:2-5, 196:12-16). The disintegration
13
Dissolution is the absorption or release of a particular analyte into the medium, which is
quantitated. (Tr. 153:11-20).
16
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 18 of 58 PageID #: 8171
caused the pH to change “pretty much instantaneous[ly]” and remained stable once dissolution
began. (Tr. at 153:25-154:5).
73.
Dr. Myers used hydrochloric acid to adjust the pH before addition of the tablet to
account for the effect on pH during tablet disintegration. (Tr. at 154:15-25; PTX-245 at 11-12).
After disintegration of Teva’s ANDA Product took place, the pH of the test media stabilized to 3.
(Tr. at 166:24-167:8, 184:2-7).
74.
The pH of the test media was 3 when dissolution testing per EP 2.9.3 began and
that pH was maintained for the duration of the dissolution testing. (Tr. at 166:24-167:8, 184:2-7;
196:17-21).
75.
The Court’s claim construction of the phrase “iron release rate below 2.5% w/w”
does not impose a pH requirement prior to the start of dissolution testing per EP 2.9.3. (D.I. 114
at 7-9).
76.
Dr. Myers conducted iron release testing on Teva’s ANDA product using an
Agilent ’08DS dissolution instrument with a paddle configuration, which complies with the
requirement of an Apparatus 2 in EP 2.9.3. (Tr. at 146:19-147:14; PTX-246 at 5-6; PTX-249 at 2).
77.
Dr. Myers conducted iron release testing on Teva’s ANDA product by conforming
to the standard test parameters as set forth in EP 2.9.3. (Tr. at 148:13-149:15; PTX-246 at 5-6;
PTX-249 at 2).
78.
Dr. Myers measured the iron content using titration after 2 hours in media at a pH
of 3. (Tr. at 149:16-150:14). The pH of the test media was 3 when dissolution testing per EP 3.9.2
began and that pH was maintained for the duration of the dissolution testing. (Tr. at 166:16167:16, 184:2-7, 195:24-196:5, 196:17-21).
17
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 19 of 58 PageID #: 8172
79.
Dr. Myers measured iron release at a pH that ranged from 3.22 to 3.28 across
6 tablets of Teva’s ANDA product, with an average pH of 3.25. (PTX-245 at 13-17; Tr. at 160:520). The 6 tested tablets of Teva’s ANDA product had an average iron release rate of 1.94% w/w,
ranging from 1.51 to 2.35% w/w. (Id.). Each of the 6 tested tablets of Teva’s ANDA product had
an iron release rate below 2.5% w/w. (Tr. at 167:9-16; PTX-245 at 13-17).
80.
Teva relies on two documents Plaintiffs submitted to the FDA as part of the New
Drug Application for Velphoro to critique Dr. Myer’s testing: PTX-323 (“Section 2.3 Quality
Overall Summary 2.3.S Drug Substance PA 21 Chewable Tablet” (dated November 27, 2017))
and DTX-69 (“3.2.P.5.3 Validation of the Determination of Iron Release in PA21 Chewable
Tablets (PA21, Chewable Tablets)” (dated November 21, 2012)).
81.
Neither DTX-69 nor PTX-323 informs a POSA how to perform the iron release test
detailed in the ’251 patent, which must be measured in water at a pH of 3 according to European
Pharmacopeia chapter 2.9.3.
82.
Both PTX-323 and DTX-69 specify the pH to two significant digits along with a
permitted range: “pH 3.0 ± 0.1.” (PTX-323 at 79; DTX-69 at 15). The ’251 patent, in contrast,
states only that the pH is “3” after 2 hours upon iron release measurement. (JTX-0001 at 14:4015:20).
83.
A POSA reading PTX-323 and DTX-69 would understand that the test methods
described in those exhibits require a pH range of “3.0 +/- 0.1,” which is different from a pH range
of 2.5-3.4, the range encompassed by “pH 3.” (Tr. at 194:4-195:15).
84.
Additionally, EP 2.9.3 states that “[a] stirring speed of between 50 r/min and
100 r/min is normally chosen; it must not exceed 150 r/min.” (PTX-246 at 12). DTX-69, on the
18
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 20 of 58 PageID #: 8173
other hand, requires “[s]uspend[ing] the tablets (agitating speed 250 rpm for PA21 FP . . .).”
(DTX-69 at 15).
85.
Similarly, EP 2.9.3 restricts the dosage number to a single dosage unit in each
vessel, instructing to “[p]lace 1 dosage unit in the apparatus.” (PTX-246 at 7). In contrast, DTX69 describes the use of multiple dosage units in a vessel. (DTX-69 at 2 (“analysing 6 samples
(each consisting of 2 tablets)”); DTX-69 at 10 (“Preparations” include “2x4 tablets”)).
86.
A POSA reviewing PTX-323 and DTX-69 would conclude that “it’s not the same
test method” as that described in the ’251 patent. (Tr. at 195:9-15).
87.
Teva’s ANDA product has an iron release rate of below 2.5% w/w as that term has
been construed by the Court and satisfies each and every element of claim 30 of the ’251 patent.
G.
Facts Relevant to Invalidity
1.
The Prior Art
a.
88.
U.S. Patent No. 6,174,442 (JTX-3)
U.S. Patent No. 6,174,442 (“the ’442 patent”) is titled “Adsorbent for Phosphate
from an Aqueous Medium, Production and Use of Said Adsorbent” and issued on
January 16, 2001.
89.
The ’442 patent “is a compound patent that describes phosphate adsorbent
containing beta iron hydroxide stabilized by carbohydrate and/or humic acid.” (Tr. at 654:20-24).
90.
The European equivalent to the ’442 patent, EP 0868125, is referenced in the
Background section of the ’251 patent. (Tr. at 655:19-56:1; JTX-1 at 1:27-37). The disclosure of
EP 0868125 is equivalent to the disclosure of the ’442 patent. (Tr. at 655:19-56:1). The ’251
patent states that EP0868125 describes “new and effective phosphate adsorbers” with “superior
19
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 21 of 58 PageID #: 8174
phosphate adsorption capacity” that “have been shown to be efficient oral phosphate binders in the
treatment of hyperphosphataemia.” (JTX-1 at 1:27-37)
91.
As the inventors of the ’251 patent explained after describing EP0868125, however,
“phosphate adsorbers with high iron loadings are still not available. Factors, such as ease of
administration in general, unacceptable taste, as well as storage and stability problems, limit the
applicability of currently available phosphate binders.” (JTX-1 at 1:38-44; Tr. at 656:10-18,
647:25-649:8).
92.
The ’442 patent does not describe any finished dosage forms. (Tr. at 654:25-
93.
The ’442 patent discloses a genus of novel phosphate adsorbents containing
655:1).
stabilized iron oxy-hydroxide. Specifically, the ’442 patent discloses that “[t]he object of the
present invention is therefore to provide adsorbents for phosphate from aqueous medium. . . . It
has been shown that this object can be achieved by the adsorbents for phosphate from aqueous
medium, to which the present invention firstly relates, which contain poly-nuclear beta-iron
hydroxide stabilised by carbohydrates and/or by humic acid.” (JTX-3 at 1:40-52).
94.
The ’442 patent identifies at least twelve different potential stabilizing agents,
including humic acid, amylopectin, “agarose, dextran, dextrin, dextran derivatives, cellulose and
cellulose derivatives, saccharose, maltose, lactose or mannitol.” (JTX-3 at 2:54-57). “Saccharose”
and “sucrose” are synonymous and refer to the same compound. (See, e.g., Tr. at 390:4-10, 400:57).
95.
The examples of the ’442 patent disclose embodiments of six phosphate adsorbents.
(JTX-3 at 3:30-6:45; 9:29-53).
20
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 22 of 58 PageID #: 8175
96.
Example 1 of the ’442 patent describes the bulk synthesis of 208.3 g of an iron oxy-
hydroxide suspension, to which 15 g of saccharose and 15 g of starch were added, yielding 47.2 g
of powder. (JTX-3 at 3:30-51).
97.
Example 1 is not a finished dosage form. (Tr. at 677:21-25). The material of
Example 1 is made by rotary evaporation. (JTX-3 at 3:45-50). As Dr. Williams explained, the
’442 patent Example 1 material “was concentrated at 50 degrees C in a rotary evaporator and dried
at 40 degrees C under high vacuum” based on his experience when material is “dried from that
rotary evaporator, you have to literally scrape it off the sides of the inside of the vessel of the rotary
evaporator” and thus would not represent a finished dosage form. (Tr. at 677:21-678:18). The
material of Example 1 would require additional processing before it would be suitable for
formulating as a finished dosage form. (Tr. at 678:19-679:7).
98.
Example 2 of the ’442 patent measures the phosphate binding capacity of the
material prepared in Example 1 containing iron oxy-hydroxide, starch, and sucrose for inorganic
phosphate. (JTX-3 at 3:53-4:13, as recorded in Table 1).
99.
Example 6 of the ’442 patent describes the bulk synthesis of a powder consisting
of 30.0 g saccharose added to the suspension of Example 1 consisting of 208.3 g iron oxyhydroxide. (JTX-3 at 5:24-30). Phosphate binding data for the Example 6 formulation is provided
in Table 5. (JTX-3 at 5:33-44). The Example 6 material had the best phosphate binding capacity
of any of the stabilized iron oxy-hydroxides disclosed in the ’442 patent. (Tr. at 663:1-5; JTX-3
at 5:33-44).
100.
Example 7 of the ’442 patent describes the bulk synthesis of a powder consisting
of 30.0 g amylopectin added to the suspension of Example 1 consisting of 208.3 g iron oxyhydroxide. (JTX-3 at 5:44-50). Phosphate binding data for Example 7 is provided in Table 6.
21
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 23 of 58 PageID #: 8176
101.
Example 8 of the ’442 patent describes the bulk synthesis of a powder consisting
of only iron oxy-hydroxide and white dextrin. (JTX-3 at 5:64-6:5). Phosphate binding data for
the Example 8 formulation is provided in Table 7. (JTX-3 at 6:6-17). Example 8 had the second
best phosphate adsorption data in the ’442 patent. (Tr. at 663:6-15; JTX-3 at 6:6-17).
102.
A POSA would understand from this data that Examples 6 (sucrose) and 8 (dextrin)
have the best phosphate binding capacity. (Tr. at 399:11-20, 663:1-15).
103.
The only stabilizers claimed in the ’442 patent are dextrin and sucrose.
Specifically, claim 7 is directed to “[a] process according to claim 2, wherein the carbohydrate
comprises saccharose or dextrin or a mixture thereof.” (JTX-3 at 12:1-2). The inventors of the
’442 patent did not specifically claim the combination of starch and sucrose as used in Example 1.
(JTX-3 at 10:36-12:24).
104.
A POSA reading the ’442 patent in its entirety would understand that the ’442
inventors considered the disclosed phosphate binders stabilized with sucrose (Example 6) and
dextrin (Example 8) to be the most promising active ingredients for development into a complete
formulation. (Tr. at 663:1-664:16, see also Tr. at 411:2-12, 399:11-20; 391:20-392:9).
105.
The ’442 patent contains a generic teaching applicable to all of the stabilized iron
oxy-hydroxides described that the novel stabilized iron oxy-hydroxides described can be
“formulated for oral application . . . They can be formulated as such or together with customary
drug additives, such as customary carriers or auxiliary materials.” (JTX-3 at 3:9-13). Also,
“[e]ncapsulation may be effected” or “the adsorbents” may be provided “together with auxiliary
materials and additives, as granules, tablets, dragees or contained in sachets.” (Id.). Because the
’442 patent refers generally to “[t]he adsorbents according to the invention” in that statement, a
22
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 24 of 58 PageID #: 8177
POSA would understand that this disclosure refers to all of the stabilized iron oxy-hydroxides
disclosed in the ’442 patent, not just Example 1. (Tr. at 392:23-393:8).
b.
106.
Hergesell (JTX-7)
In 1999, Hergesell and Rich published an article titled “Stabilized polynuclear iron
hydroxide is an efficient oral phosphate binder in uraemic patients” in Nephrology Dialysis
Transplantation (“Hergesell”). (JTX-7).
107.
The ’251 patent discusses Hergesell. (JTX-1 at 1:31-37; Tr. at 656:2-9). In the
paragraph immediately following that discussion, the ’251 patent states that “phosphate adsorbers
with high iron loadings are still not available. Factors, such as ease of administration in general,
unacceptable taste, as well as storage and stability problems, limit the applicability of currently
available phosphate binders.” (JTX-1 at 1:38-44; Tr. at 656:10-18).
108.
Hergesell describes an open uncontrolled study of the efficacy and tolerability of
“stabilized polynuclear iron hydroxide.”
(JTX-7).
Hergesell discloses that a “stabilized
polynuclear iron hydroxide” of the chemical formula “[FeO2/3(OH)5/3H2O l/m(C6H10O5)m]n”
“appears to be a promising, new compound which has remarkable in vitro binding capacity for
phosphate compared to the cross-linked iron Dextran.” (JTX-7 at 1; Tr. at 402:4-16). Aside from
this chemical formula, Hergesell does not provide any other details about the “stabilized
polynuclear iron hydroxide” used in the clinical study. (JTX-7).
109.
The POSA “having looked at the ’442 Patent, and Hergesell sees that Hergesell
discloses that there are promising compounds that have remarkable in vitro binding capacity” and
“they would also see that they were given a formula with respect to the promising new compound.”
(Tr. at 402:12-19).
23
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 25 of 58 PageID #: 8178
110.
The chemical formula in Hergesell (“[FeO2/3(OH)5/3H2O l/m(C6H10O5)m]n”)
contains “two different chemical compounds,” one on the left and one on the right, and the
chemical compound on the right is “(C6H10O5)m.” (JTX-7 at 1; Tr. at 403:8-404:11).
111.
C6H10O5 is consistent with starch, amylopectin and dextrin. (Tr. at 404:12-405:6,
406:25-407:2). Amylopectin and dextrin are the stabilizers used in Examples 7 and 8 of the ’442
patent. (JTX-3 at 5:44-50, 5:64-6:5; Tr. at 405:15-17, 407:3-10).
112.
In describing “stabilized polynuclear iron hydroxide,” Hergesell cites DE 195 47
356 A1 (designated as footnote 13). (JTX-7 at 1, 4).
113.
DE 195 47 356 A1 is the German patent application to which the ’442 patent claims
priority. (Tr. at 307:1-6).
114.
The chemical formula C6H10O5 is not consistent with sucrose or saccharose. (Tr. at
668:2-5). The chemical formula for saccharose is C12H22O11. (Tr. at 409:12-15).
115.
Hergesell does not disclose the chemical formula C12H22O11 (saccharose). (Tr. at
409:16-18). There is no disclosure of saccharose in Hergesell. (Tr. at 409:19-21).
116.
The components of the “stabilized polynuclear iron hydroxide” in the chemical
formula in Hergesell are consistent with Examples 7 and 8 of the ’442 patent but not consistent
with the components for sucroferric oxy-hydroxide (described in Example 1 of the ’442 patent).
(See 404:12-25, 405:15-23, 407:3-10, 668:2-5, 672:22-673:9).
117.
Hergesell discloses that “powder in pre-weighed sachets were provided to patients”
(Tr. at 685:21-668:1) and that patients were “given a constant dose of 3 x 2.5 g stabilized
polynuclear iron hydroxide” (JTX-7 at 2). From this disclosure, however, “it’s just not clear” how
“much of the stabilized polynuclear iron oxyhydroxide is contained in each preweighed sachet.”
(Tr. at 686:2-15; JTX-7 at 2).
24
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 26 of 58 PageID #: 8179
c.
118.
U.S. Patent No. 4,970,079 (“the ’079 patent”) (JTX-5)
The ’079 patent is titled “Method and composition of oxy-iron compounds for
treatment of hyperphosphatemia” and issued on November 13, 1990. (JTX-5 at 1).
119.
The ’079 patent discloses “three types of oxy-iron compounds . . . iron oxides, iron
hydroxide and iron oxyhydroxides.” (Tr. at 686:19-23; JTX-5 at 3:12-14). The ’079 patent
discloses “500 mg or more” of such compounds. (JTX-5 at 3:52-55; Tr. at 686:24-687:10).
120.
The foreign equivalent to the ’079 patent is referenced in the Background section
of the ’251 patent. (Tr. at 657:13-19; JTX-1 at 2:4-18). There, the ’251 patent states that “[n]o
specific oral formulations are disclosed” in the ’079 patent, that “no specific iron loading is
mentioned” and that, although there is a disclosure that “each oral dose may contain 50 mg to
about 500 mg or more of oxy-iron compound,” “[a]ccording to the state of the art tablets containing
500 mg oxyiron compounds . . . would be of such an enormous size that they could not be
swallowed by the patient.” (JTX-1 at 2:4-18; Tr. at 657:20-658:6).
121.
“The ’079 patent relates to unstabilized oxy-iron compounds. In the ’079 patent,
there is no disclosure of stabilized iron oxyhydroxide and there is no specific disclosure of how to
formulate and make finished dosage forms.” (Tr. at 656:19-657:2).
122.
The ’079 patent also teaches that “each oral dose of the therapeutic oxy-iron
containing composition in accordance with this invention can contain from about 50 milligrams to
about 500 milligrams or more of oxy-iron compound” and that the “amount of oxy-iron compound
to be administered will depend on the severity of the patient’s condition, the nature of the patient’s
diet, and the surface area and phosphate binding capacity of the specific oxy-iron compound used
in the formulation.” (Tr. at 686:24-687:10).
25
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 27 of 58 PageID #: 8180
123.
The ’079 patent also discloses that “a 174-milligram dose of ferrihydrite can absorb
the same amount of phosphate of ten mil as . . . Amphogel which is a commercially available
aluminum hydroxide product. And it mentions a tablet or capsule containing 174 milligrams of
synthetic ferrihydrite.” (Tr. at 687:11-688:2). However, “the ’079 [patent] does not give any
details how to formulate a composition that contains 174 milligrams of ferrihydite [sic:
ferrihydrite] or a method of how to make a composition.” (Tr. at 688:3-8).
124.
The only disclosure in the ’079 patent regarding how to formulate tablets or
capsules containing the oxy-iron compounds is a single passage that states “methods and excipients
for preparation of both gel and solid dosage forms are well-known in the art.” (Tr. at 688:19689:2). “[T]hat’s [] a really general statement” that “doesn’t really tell a POSA how specifically
to formulate or make dosage forms of the oxy-iron compounds of this invention.” (Tr. at 689:25).
125.
The ’079 patent does not give any specific details about how to formulate a
composition that contains 174 milligrams of ferrihydrite or a method of how to make a
composition. (Tr. at 688:3-8).
126.
The ’079 patent claims “[a] therapeutic composition in oral dosage form for
controlling serum phosphate in patients having need for reduced absorption of dietary phosphate,
said composition comprising on a per dose basis from about 50 mg to about 500 mg of an oxyiron
compound selected from the group consisting of iron oxides, iron oxyhydroxides, and iron
hydroxides, and a pharmaceutically acceptable excipient for said oral dosage form.” (JTX-5 at
7:18-8:2).
26
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 28 of 58 PageID #: 8181
2.
127.
Obviousness of the Asserted Claims Based on the ’442 Patent Alone
Independent claims 1 and 27 of the ’251 patent both require “wherein the amount
of iron oxy-hydroxide per dosage form is at least 500 mg.” Each asserted claim is dependent on
either claim 1 or 27 and, thus, incorporate by reference the “wherein the amount of iron oxyhydroxide per dosage form is at least 500 mg” limitation. (FF ¶¶ 21-28). Claims 29, 30, and 33
of the ’251 patent require a “pharmaceutical composition” with “at least 500 mg” of iron oxyhydroxide “per dosage form” while claim 56 – which is dependent on claim 27 – further requires
a higher amount of “about 800 mg iron oxy-hydroxide per dosage form.” (Id.). Thus, all asserted
claims require a “pharmaceutical composition” with “at least 500 mg” of iron oxy-hydroxide “per
dosage form.” (Id.).
128.
A POSA would not have been motivated to make a single dosage form with at least
500 mg or about 800 mg of iron oxy-hydroxide based on the disclosure of the ’442 patent. (Tr. at
697:4-12).
129.
The ’442 patent does not disclose any complete pharmaceutical compositions, let
alone any high loaded compositions. (See Tr. at 654:25-655:1).
130.
Example 1 describes the bulk synthesis of 47.2 g of SFO. (JTX-3 at 3:45-50). Thus,
a POSA attempting to formulate Example 1 would need to select the amount of iron oxyhydroxide
to include per dosage form. (See Tr. at 679:17-22).
131.
“There is no discussion in Example 1 about how much iron oxyhydroxide from the
powder that’s been produced should be loaded in a final dosage form.” (Tr. at 679:20-22).
132.
The ’442 patent generically discloses that “[t]he daily dose of the adsorbents
according to the invention is, for example, 1 to 3 g, preferably about 1.5 g of iron.” (JTX-3 at
3:19-21). A POSA would understand that this disclosure is directed to the entire class of disclosed
27
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 29 of 58 PageID #: 8182
stabilized iron oxy-hydroxide compounds. (See Tr. at 392:23-393:8). 500 mg of iron corresponds
to 800 mg of iron oxyhydroxide. (See FF ¶ 32).
133.
Applying the generic disclosure of a preferred “daily dose” of “1.5 g of iron” (JTX-
3 at 3:19-21) to all of the Examples would result in significantly different phosphate binding
capacities at that single preferred daily dose. The Examples have different phosphate binding
capacities – ranging from 100% to 69% at pH 3 and 100% to 65% at pH 5.5. (JTX-3 at 4:1-13,
5:33-44, 5:52-63, 6:6-17, 6:32-44, 9:40-52; Tr. at 662:19-663:21). This means that a 1.5 g daily
dose of Example 8 would have about 30% more phosphate binding capacity than a 1.5 g daily dose
of Example 7.
134.
As Dr. Williams explained, the determination of the correct dose is determined
during pre-formulation testing and is based on a number of factors, which would likely require
testing and input from a physician. (Tr. at 659:11-660:3, 685:3-15; DTX-1006 at 4, 12). The ’442
patent does not provide this information. (Tr. at 685:16-20).
135.
Dr. Rastogi, a physician, explained that administering high doses of iron is
particularly challenging because it can cause gastrointestinal irritation. (Tr. at 512:24-513:3; see
also JTX-1 at 2:49-53).
136.
For example, iron compositions “more often than not cause[] gastrointestinal
problems,” and 500 mg per dose is significantly higher than the “normal requirement [of] one
milligram per day absorption of iron.” (Tr. at 513:1-6).
137.
The ’442 patent provides no teaching about the number of administrations per day
for the preferred daily dose. (Tr. at 680:9-680:16, 684:6-20). Rather, a POSA would understand
this “to refer to the total daily dose” and would understand that it “doesn’t provide guidance to a
28
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 30 of 58 PageID #: 8183
POSA on . . . how to subdivide it into dosage forms. It just doesn’t give that information.” (Tr. at
680:12-16).
138.
The ’442 patent teaches generally in claim 12 that the claimed phosphate binders
should be taken “simultaneously with intake of food.” (JTX-3 at 12:13-17). That does not inform
a POSA of the number of administrations per day. (See Tr. at 684:9-20).
139.
As Dr. Williams explained, a POSA would understand this teaching to mean
exactly what it is says – i.e., “take the stabilized polynuclear beta iron oxyhydroxide when they
eat food.” (Tr. at 684:12-14).
140.
There is nothing in the ’442 patent disclosure that equates ingesting food at regular
meals, let alone three meals per day. Dr. Fadem acknowledged that patients take phosphate binders
not just with meals but with some snacks as well. (Tr. at 733:3-734:4).
141.
The labels for other phosphate binders do not establish “general knowledge” among
POSAs that phosphate binders are administered three times a day. First, a POSA would not look
to the dosing regimens of non-iron based phosphate binders when seeking to formulate the
stabilized iron oxy-hydroxide binders described in the ’442 patent. (Tr. at 696:1-20). Second,
three of the four labels on which Teva relies are not prior art. These three labels have revision
dates of 2011 – years after the 2007 filing of the priority application to the ’251 patent. (PTX-217
at 1, PTX-544 at 1, PTX-211 at 1). Two of the four labels upon which Teva relies state that the
dosage and administration information was changed in 2009 and 2011, respectively. (PTX-217 at
1; PTX-544 at 1).
142.
Third, even if a POSA did rely on those labels, they show that phosphate binders
frequently have multiple doses that depend on a number of patient-specific factors. (PTX-217 at
1-3; PTX-544 at 1-2; PTX 211 at 1-2; PTX-214 at 1-3; DTX-120 at 1-3; Tr. at 722:15-723:9). For
29
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 31 of 58 PageID #: 8184
example, Renagel® was administered as up to five tablets per administration. (PTX-214 at 1-3).
Similarly, even sachets and oral suspensions required multiple dosage forms – the 1.6 g starting
dose for Renvela® was administered as two 0.8 g sachets. (Tr. at 722:15-723:9; DTX-120 at 1;
PTX-217 at 1). Additionally, PhoslyraTM was administered as two 5 ml oral suspensions. (PTX211 at 1).
143.
As Dr. Williams explained, once the appropriate dose is set, a POSA still needs to
determine whether it can be delivered in a single dosage form, and the ’442 patent provides no
information about these formulation considerations. (Tr. at 685:3-20). For example, once a POSA
determines the correct dose administration, the POSA would then consider a number of
formulation factors to determine if that dose can be formulated in a single dosage unit or whether
the dose needs to be divided among multiple dosage units. (Id). The ’442 patent “doesn’t give []
information” about whether “it’s possible to load any given amount of iron oxyhydroxide [into] a
given dosage form.” (Id.).
144.
A POSA would not have had a reasonable expectation of success in formulating a
high loaded composition with “at least 500 mg” or “about 800 mg” of iron oxy-hydroxide per
dosage form. (Tr. at 697:13-18).
145.
Thus, a POSA would not have had reason to believe that a single dose containing
500 or 800 mg iron oxy-hydroxide would be successful as a pharmaceutical formulation. (See
Tr. at 512:13-513:19 (noting that compressing 500 milligrams of iron in a small tablet is
“remarkable,” particularly given the “very minimal” gastrointestinal adverse events); 697:13-18).
30
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 32 of 58 PageID #: 8185
3.
146.
Obviousness of the Asserted Claims Based on the ’442 Patent in
Combination with Other Prior Art
Teva relies on one or more of Hergesell and the ’079 patent in combination with
the ’442 patent to argue that a combination of prior art references render the “wherein the amount
of iron oxy-hydroxide per dosage form is at least 500 mg” limitation of the asserted claims obvious.
147.
The Hergesell reference and ’079 patent do not teach or suggest the limitations that
are not disclosed in or rendered obvious by the ’442 patent.
148.
None of the other cited prior art references contain any specific pre-formulation
data related to sucroferric oxyhydroxide. (Tr. at 660:4-17). Moreover, none of the other cited
prior art references contain any pre-formulation data related to any of the stabilized polynuclear
iron oxyhydroxides described in the ’442 patent generally. (Tr. at 660:18-661:2).
149.
Aside from the ’442 patent, Hergesell is the only prior art reference Teva relies on
that discusses stabilized iron oxy-hydroxide. (Tr. at 677:8-14).
a.
150.
The Relationship Between the ’442 Patent and Hergesell
Dr. Chambliss testified that “[a]s a formulator, you would start with the ’442 Patent
and then you would look to see if there is any other publications out there which use that material,
and you would find Hergesell. And Hergesell then directs you back to the ’442 Patent. So they’re
very tightly tied together.” (Tr. at 306:1-5). Accordingly, a POSA reviewing the ’442 patent
would also review and consider the disclosure in Hergesell.
151.
Hergesell explicitly references the German priority application that corresponds to
the ’442 patent. (JTX-7 at 1; see also Tr. at 307:1-6).
152.
Hergesell states that a “stabilized polynuclear iron hydroxide” having the chemical
formula “[FeO2/3(OH)5/3H2O l/m(C6H10O5)m]n” “appears to be a promising, new compound which
31
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 33 of 58 PageID #: 8186
has remarkable in vitro binding capacity for phosphate compared to the crosslinked iron dextran.”
(JTX-7 at 1; Tr. at 402:4-16).
153.
The POSA “having looked at the ’442 Patent, and Hergesell sees that Hergesell
discloses that there are promising compounds that have remarkable in vitro binding capacity” and
“they would also see that they were given a formula with respect to the promising new compound.”
(Tr. at 402:12-19).
154.
Dr. Chambliss agreed that the chemical formula on the first page of Hergesell
describes two different chemical compounds – FeO2/3(OH)5/3H2O and C6H10O5. (Tr. at 403:18404:11).
155.
Dr. Chambliss acknowledged that the formula (C6H10O5)m is consistent with
amylopectin and dextrin. (Tr. at 405:3-6; 406:25-407:2). Amyolpectin and dextrin are the
stabilizers used in Examples 7 and 8 of the ’442 patent. (Tr. at 405:15-17; 407:3-10).
156.
Dr. Chambliss also acknowledged that the Hergesell chemical formula is not
consistent with sucrose (saccharose) and that there is no disclosure of sucrose anywhere in
Hergesell. (Tr. at 409:12-21; 410:19-25). Thus, the chemical formula in Hergesell is not
consistent with Example 1 of the ’442 patent.
157.
Because the Hergesell formula does not include sucrose and is inconsistent with
Example 1 of the ’442 patent, it would lead a POSA away from selecting Example 1 as the active
ingredient for formulation development.
158.
A POSA would not discount the Hergesell formula because its description of the
iron-based compound is, according to Teva, “non-standard and erroneous.” Dr. Chambliss agreed
that he could understand the right side of the formula and that it describes a carbohydrate. (Tr. at
403:8-405:2).
32
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 34 of 58 PageID #: 8187
b.
159.
The ’442 Patent in combination with Hergesell and the ’079
Patent do not teach or suggest “wherein the amount of iron oxyhydroxide per dosage form is at least 500 mg”
Teva contends that the ’079 patent and Hergesell provide motivation for a POSA
to make a formulation with at least 500 mg or about 800 mg of sucroferric oxyhydroxide per
dosage form. Neither reference motivates a POSA to include 500 mg or 800 mg of iron oxyhydroxide in a single dosage form.
160.
The ’079 patent discloses “three types of oxy-iron compounds . . . iron oxides, iron
hydroxide and iron oxyhydroxides.” (JTX-5 at 3:12-14; Tr. at 686:19-23). The ’079 patent
discloses “500 mg or more” of such compounds. (JTX-5 at 3:52-55; Tr. at 686:24-687:10). The
’079 patent, however, does not disclose any finished dosage formulations, nor does it teach how
to formulate the disclosed iron oxy compounds. (Tr. at 688:9-689:5).
161.
The ’079 patent also teaches that 174 mg of iron oxy compound is as effective in
adsorbing phosphate as the commercially available aluminum hydroxide product and mentions a
tablet or capsule containing 174 milligrams of iron oxy compound. (Tr. at 687:14-688:2).
162.
However, “[t]he ’079 [patent] does not give any details about specifically how to
formulate a composition that contains 174 milligrams of ferrihyd[rite] or a method of how to make
a composition.” (Tr. at 688:3-8).
163.
Hergesell discloses that “powder in pre-weighed sachets were provided to patients”
(Tr. at 685:21-686:1) and that patients were “given a constant dose of 3 x 2.5 g stabilized
polynuclear iron hydroxide” (JTX-7 at 2). From this disclosure, it is not clear how much powder
is contained in each sachet. (Tr. at 686:2-7). It is also not clear “how much of the stabilized
polynuclear iron oxyhydroxide is contained in each pre-weighed sachet.” (Tr. at 686:8-15).
33
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 35 of 58 PageID #: 8188
4.
Objective Indicia of Nonobviousness
a.
164.
Long Felt But Unmet Need
The search for safe and effective phosphate binders began in the 1970s. (Tr. at
507:8-18).
165.
Aluminum-based binders were the first binders that were widely used for treating
hyperphosphatemia. (Tr. at 493:21-25). Aluminum-based binders were effective but could be
toxic because the aluminum is absorbed into the body. (Tr. at 494:15-17). This risk of aluminum
toxicity led to discontinuation of widespread use of aluminum-based binders. (DTX-1019 at 3-4).
166.
In the 1990s, calcium-based binders began to be used as a replacement for
aluminum-based binders. (Tr. at 497:21-498:18; DTX-1019 at 5). Calcium-based binders,
however, are also associated with adverse events including hypercalcemia, vascular calcification,
and bone disease resulting from the systemic absorption of calcium. (Tr. at 498:24-499:2-16;
DTX-1019 at 5). As of at least 2014, the medical field was warned that calcium-based binders
should be avoided altogether. (Tr. at 499:17-24; DTX-1019 at 5; PTX-446 at 31).
167.
Sevelamer-based binders are nonmetal binders in the class of polymers. (Tr. at
502:3-13). These binders are safe but not very effective so they must be administered in very large
pills. (Tr. at 502:24-504:5). The large pills can result in poor patient compliance and poor
therapeutic outcomes. (Id.).
168.
Lanthanum-based binders are metal-based. (Tr. at 504:7-505:3). Lanthanum-based
binders are more effective than calcium and sevelamer but, as warned on package inserts,
lanthanum is difficult to chew and can result in broken teeth, which actually led to noncompliance
and discontinuation. (Id.; PTX-544 at 1-3).
34
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 36 of 58 PageID #: 8189
169.
Aluminum-based, calcium-based, sevelamer-based, and lanthanum-based binders
each failed to satisfy the need for a safe, effective, and tolerable binder. (Tr. at 506:16-507:1).
170.
Velphoro satisfied the long-felt need for a safe, effective, and tolerable binder.
(Tr. at 507:2-4).
171.
Velphoro was able to get patients to their goal serum phosphate levels through
administration of a reasonably sized, easy-to-chew tablet with a low pill burden, all of which are
important for long-term compliance and efficacy. (Tr. at 508:20-509:21, 511:6-23; DTX-1020 at
2).
172.
Despite being a metal-based binder, Velphoro was safe due to little to no systemic
bioabsorption and thus, no iron toxicity. (Tr. at 508:14-18).
b.
173.
Commercial Success
Velphoro has substantial revenues from its sales in the United States since launch
to September 2019, achieving net sales of approximately $481 million. (Tr. at 566:10-20).
174.
Velphoro’s sales have grown rapidly from about $15 million in the partial year
2014, the year of launch, to $135 million in annual sales through September 2019. That growth
reflects a compound annual growth rate of about 35%. (Id.; DTX-313-F at 1; DTX-697).
175.
These sales provide evidence of marketplace success. (Tr. at 567:2-4).
176.
Velphoro competes more closely with calcium-free binders when compared to
calcium-based binders. (Tr. at 569:2-12, 616:8-617:2; DTX-493, DTX-879, DTX-836).
177.
Velphoro’s share of the calcium-free segment rose from just under 2% in the year
of launch to 11.8% in September 2019. (Tr. at 569:22-570:19, 575:25-576:10). Velphoro’s shares
of prescriptions in the calcium-based binder market shows a similar growth pattern and similar
trajectory, rising to 8% in September 2019. (Tr. at 575:25-576:10; DTX-697; DTX-313-M at 1).
35
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 37 of 58 PageID #: 8190
178.
Velphoro’s market is characterized by competition among branded and generic
pharmaceutical products. (Tr. at 571:7-23). Generic products have substantially lower prices.
(Id.).
179.
Velphoro was a late entrant to a relatively crowded field of phosphate binders,
including both generic and branded competitors. (Tr. at 573:3-13). Being a late entrant results in
more limited market uptake than one would expect if one was an early entrant. (Tr. at 574:9-18).
180.
The marketplace success of Velphoro based on its ability to penetrate the market
despite being a late entrant and in the face of significant generic competition provides further
confirmation of its success in the marketplace. (Tr. at 575:3-11).
c.
181.
Blocking Patent
Teva asserts that the ’442 patent is a “blocking patent, which disincentivized others
from developing the alleged invention” and “further limits” the asserted objective indicia.
(D.I. 299 at 27-28).
182.
The claims of the ’442 patent are limited to the beta form of sucroferric
oxyhydroxide, and thus the ’442 patent would block entry in the marketplace with respect to only
the beta form. (Tr. at 749:23-750:2, 634:11-14; JTX-3 at claim 1).
183.
In contrast, the ’251 patent includes other forms of the active ingredient, including
alpha and gamma. (Tr. at 634:15-21; JTX-1 at claim 1 et al).
184.
Teva offered no evidence that those in the industry were prevented from practicing
the ’251 patent due to the ’442 patent.
5.
185.
Enablement of Claims 29 and 30
Claim 29 requires the “composition according to claim 1, wherein the iron
oxyhydroxide is essentially non-bioabsorbable.” (JTX-1 at 17:18-19).
36
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 38 of 58 PageID #: 8191
186.
The Court construed “essentially non-bioabsorbable” to mean “[u]pon oral
administration, the iron oxyhydroxide is not absorbed by the human body in a clinically significant
amount.” (D.I. 114 at 5).
187.
A clinician would understand that “clinically significant” means that “there is an
effect of the drug . . . that changes the practice. And if there is iron absorption that it would change
the way this drug is used and that’s why the prescribing information is very important.” (Tr. at
107:21-108:11).
188.
Dr. Rastogi gave an example of an iron uptake amount that was “quite low and
insignificant” – 0.04%. (Tr. at 103:17-104:2). He also gave an example of a drug with clinically
significant iron release – “[i]f you’re given a drug like Auryxia, you would expect the iron to be
absorbed, not the iron levels to go down.” (Tr. at 135:10-12).
189.
A POSA would understand that clinical significance is determined by looking at
the averages across the patient population, not any outcome for an individual patient. (Tr. at 134:1136:3).
190.
A POSA, following the disclosure in the ’251 patent, could generate the claimed
compositions that are essentially non-bioabsorbable without undue experimentation. The ’251
patent provides numerous working examples of complete formulations, including chewable tablets
with iron release rate as low as 0.2% (product 8g). (JTX-1 at 14:1-15:20). Dr. Chambliss
explained that iron release rate and bioabsorbability go “hand in hand” such that if iron release is
higher, the absorption is higher. (Tr. at 300:20-24). Thus, a POSA would understand that the
tablets taught in the working examples of the ’251 patent would be expected to be nonbioabsorbable.
In addition, Example 2b is very similar to the formulation of Velphoro, a
37
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 39 of 58 PageID #: 8192
formulation that has been shown to be essentially non-bioabsorbable. (JTX-1 at 12:39-60; PTX322 at 10).
191.
The ’251 patent also provides guidance about manufacturing techniques that should
be avoided in order to prevent the release of iron. (JTX-1 at 8:30-33, 10:5-9).
192.
Claim 30 requires the “composition according to claim 1, having an iron release
rate of below 2.5% w/w.” (JTX-1 at 17:20-21).
193.
The Court construed “iron release rate below 2.5%” to mean “[t]he iron release
measured in water at a pH of 3 according w/w to European Pharmacopeia chapter 2.9.3 using
standard dissolution equipment and parameters as described in the monograph, where iron content
is analyzed by titration after 2 hours, wherein the quantity of iron dissolved after 2 hours is less
than 2.5% w/w.” (D.I. 114 at 7).
194.
The ’251 patent teaches that “[t]he inventive compositions have a low iron release
rate of below 2.5% w/w, which is essential for phosphate adsorbers. In contrast thereto,
compositions used for treating iron deficiency have a high iron release rate and thus are completely
different form the inventive compositions.” (JTX-1 at 3:6-11).
195.
The patent also describes an example in which “Fe release was measured according
to European Pharmacopeia chapter 2.9.3 using standard dissolution equipment and parameters as
described in the monograph.” (JTX-1 at 14:48-50). Six out of seven tablets tested had a release
rate of less than 2.5%. (JTX-1 at 15:10-20).
196.
The ’251 patent contains explicit guidance about how to make the claimed
pharmaceutical compositions, including information about the type and brand of starch that can be
used to make chewable tablets that achieve the claimed iron release rate. (JTX-1 at 14:1-15:20).
Specifically, Table 7 of the ’251 patent identifies Lycatab® pregelatinized starch as being used in
38
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 40 of 58 PageID #: 8193
chewable tablets with iron release rates below 2.5%. (JTX-1 at 14:10-23; see also Tr. at 381:1116).
197.
Accordingly, a POSA following the disclosure of the ’251 patent would be able to
readily produce compositions that satisfy claim 30.
II.
LEGAL STANDARDS
A.
Infringement
A patent is infringed when a person “without authority makes, uses, offers to sell, or sells
any patented invention, within the United States . . . during the term of the patent.” 35 U.S.C.
§ 271(a). Courts employ a two-step analysis in making an infringement determination. See
Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed. Cir. 1995). First, a court must
construe the asserted claims. See id. Next, the trier of fact must compare the properly-construed
claims to the accused infringing product. See id. Literal infringement occurs where “every
limitation in a patent claim is found in an accused product, exactly.” Southwall Techs., Inc. v.
Cardinal IG Co., 54 F.3d 1570, 1575 (Fed. Cir. 1995).
B.
Validity
An issued patent is presumed to be valid. See 35 U.S.C. § 282. Therefore, to invalidate a
patent, a party must carry its burden of proof by “clear and convincing evidence.” See Procter &
Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 993-94 (Fed. Cir. 2009). Clear and
convincing evidence is evidence that “proves in the mind of the trier of fact an abiding conviction
that the truth of [the] factual contentions [is] highly probable.” Intel Corp. v. ITC, 946 F.2d 821,
830 (Fed. Cir. 1991) (internal quotation marks omitted; first modification in original).
A
defendant’s burden to prove invalidity is “especially difficult when the prior art [on which it relies]
39
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 41 of 58 PageID #: 8194
was before the PTO examiner during prosecution of the application.” Hewlett-Packard Co. v.
Bausch & Lomb Inc., 909 F.2d 1464, 1467 (Fed. Cir. 1990).
1.
Obviousness
A patent may not issue “if the differences between the claimed invention and the prior art
are such that the claimed invention as a whole would have been obvious before the effective filing
date of the claimed invention to a person having ordinary skill in the art to which the claimed
invention pertains.” 35 U.S.C. § 103(a). Obviousness is a question of law based on underlying
factual findings concerning: (1) the scope and content of the prior art; (2) the differences between
the claims and the prior art; (3) the level of ordinary skill in the art; and (4) objective considerations
of nonobviousness. See Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966). To prove that a
patent is obvious, a party must demonstrate “that a skilled artisan would have had reason to
combine the teaching of the prior art references to achieve the claimed invention, and that the
skilled artisan would have had a reasonable expectation of success from doing so.” In re
Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1069
(Fed. Cir. 2012); see also Amgen, Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1362 (Fed.
Cir. 2009) (“An obviousness determination requires that a skilled artisan would have perceived a
reasonable expectation of success in making the invention in light of the prior art.”). Although an
analysis of any teaching, suggestion, or motivation to combine known elements is useful to an
obviousness analysis, the overall obviousness inquiry must be expansive and flexible. See KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 415, 419 (2007). The use of hindsight is not permitted
when determining whether a claim would have been obvious to one having ordinary skill in the
art. See id. at 421 (cautioning against “the distortion caused by hindsight bias” and obviousness
“arguments reliant upon ex post reasoning”). To protect against the improper use of hindsight
40
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 42 of 58 PageID #: 8195
when assessing obviousness, the Court is required to consider objective indicia of nonobviousness, such as commercial success, failure of others, unexpected results, and long-felt but
unmet need. See, e.g., Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed. Cir. 2013).
2.
Enablement
“The enablement requirement asks whether the specification teaches those in the art to
make and use the invention without undue experimentation.” Enzo Life Scis., Inc. v. Roche
Molecular Sys., Inc., 928 F.3d 1340, 1345 (Fed. Cir. 2019) (internal quotations omitted). “To be
enabling, the specification of a patent must teach those skilled in the art how to make and use the
full scope of the claimed invention without undue experimentation.” MagSil Corp. v. Hitachi
Glob. Storage Techs., Inc., 687 F.3d 1377, 1380 (Fed. Cir. 2012) (internal quotation marks
omitted).
“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).
These factors may include:
“(1) the quantity of
experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or
absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the
relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the
breadth of the claims.” Id. Although “a specification need not disclose what is well known in the
art,” “[t]ossing out the mere germ of an idea does not constitute enabling disclosure.” Genentech,
Inc. v. Novo Nordisk A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997). A patent “cannot simply rely on
the knowledge of a person of ordinary skill to serve as a substitute for the missing information in
the specification.” ALZA Corp. v. Andrx Pharm., LLC, 603 F.3d 935, 941 (Fed. Cir. 2010).
41
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 43 of 58 PageID #: 8196
III.
DISCUSSION
A.
Infringement
Vifor asserts that Teva’s ANDA product infringes claims 29, 30, 33, and 56 of the ’251
patent. As previously noted, the parties have stipulated to infringement of claims 33 and 56.
(D.I. 277, Ex. 1 ¶¶ 23, 24, 25). Thus, the Court addresses only claims 29 and 30.
1.
Claim 29
The only dispute about infringement of claim 29 is whether Teva’s proposed ANDA
product satisfies the limitation requiring “wherein the iron oxy-hydroxide is essentially nonbioabsorbable.” (FF ¶ 48). The Court construed “essentially non-bioabsorbable” to mean “upon
oral administration, the iron oxyhydroxide is not absorbed by the human body in a clinically
significant amount.” (FF ¶ 49).
Teva asserts that claim 29 requires in vivo testing to determine whether its product meets
the disputed “essentially non-bioabsorbable” limitation and argues that bioequivalence alone is not
sufficient. (E.g., D.I. 309 at 1, 3-5). It is not, however, bioequivalence alone that is at issue. Teva
has represented to the FDA that, upon oral administration, the iron oxyhydroxide formulated in its
ANDA product is not absorbed in clinically significant amounts. For instance, the proposed label
states that sucroferric oxyhydroxide in Teva’s proposed ANDA product “is practically insoluble
and therefore not absorbed and not metabolized.” (FF ¶ 52). The proposed label also includes
data from a clinical trial showing that iron uptake was “quite low and insignificant” when measured
using radiolabeled sucroferric oxyhydroxide (the only iron source in the tested product).
(FF ¶¶ 53-54).
42
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 44 of 58 PageID #: 8197
Teva argues that these statements in the proposed label are not relevant because they were
copied from the Velphoro package insert. 14 These arguments, however, ignore that Teva seeks
approval to sell a product having these attributes, which is the relevant inquiry for infringement
under 35 U.S.C. § 271(e). See Sunovion Pharm., Inc. v. Teva Pharm. USA, Inc., 731 F.3d 1271,
1278 (Fed. Cir. 2013). Moreover, as Dr. Rastogi opined, the expectation that a generic drug
behaves in the same manner as the branded drug is something that physicians rely upon when
prescribing generic drugs. (FF ¶ 55). That is particularly apparent here, where if that expectation
is not correct (i.e. if the ANDA product does not have same toxicity profile as Velphoro), patient
safety may be jeopardized. (FF ¶ 56). Thus, it strains credulity for Teva to argue that it has sought
FDA approval without knowing whether its proposed package insert accurately describes its
ANDA product (and without knowing whether its ANDA product could prove toxic to patients).15
Moreover, Teva’s proposed package insert is just one of the statements that Teva made to
the FDA relating to the non-bioabsorbability of the iron oxyhydroxide as formulated in its ANDA
product. Teva’s pharmaceutical and product development reports state that the iron is “not
available in soluble form to be absorbed in the [gastrointestinal tract].” (FF ¶¶ 58, 59). The same
reports then describe dissolution tests comparing Teva’s ANDA product to Velphoro. These tests
showed that “[b]oth test and reference did not show release in most relevant fed state pH of GI
tract” and that the results were consistent with other literature that “indicate negligible release of
14
Teva’s expert, Dr. Fadem, would not confirm that the statements in Teva’s package insert
accurately describe Teva’s ANDA product. (Tr. at 226:14-20).
15
Teva’s criticisms that Dr. Rastogi did not do in vivo testing are not well taken. It is wholly
unclear that conducting human testing for purposes of patent infringement could pass
ethical muster. (See Tr. at 114:4-20). Moreover, the Court agrees that it was fair for
Dr. Rastogi to trust the integrity of Teva’s submissions to the FDA – as Teva presumably
expects the FDA and clinicians to do. (Id.).
43
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 45 of 58 PageID #: 8198
iron in the [gastrointestinal tract] for absorption.”
(FF ¶ 58).
These statements and the
comparative study were not copied from Velphoro but appear to be Teva’s own work. Indeed,
Teva’s corporate representatives confirmed the accuracy of these conclusions, and Dr. Fadem had
no explanation for these representations Teva made to the FDA in any of these reports. (FF ¶¶ 6061).
Although Teva attempts to shrug off the statements in its proposed package insert (and
other development documents), the Federal Circuit has held that “[t]here is no basis to disregard
the information contained on the package inserts, which are representations made to the FDA to
establish that the proposed generics possess the same characteristics . . . present in [the] approved
product[].” Endo Pharm. Inc. v. Teva Pharm. USA, Inc., 731 Fed. App’x. 962, 974 (Fed. Cir.
2018). The fact that the relevant portions of Teva’s package were copied from Velphoro does not
change this analysis. In Allergan, Inc. v. Watson Labs., Inc. – Florida, 869 F. Supp. 2d 456, 51314 (D. Del. 2012), the Court rejected an argument nearly identical to the one Teva presents. As
here, the Allergan ANDA filers copied pharmacokinetic data from the reference listed drug’s
package insert. The Allergan ANDA filers argued that the Court should discount their package
inserts and instead rely on a study performed by one of their experts. Id. at 512-13. The Court
rejected this argument and found infringement based on the data from the reference listed drug
that the generics copied in their package inserts.
Similarly, here, holding Teva to the
representations made in its package insert and pharmaceutical development documents is
appropriate.
The evidence establishes that the iron oxyhydroxide as formulated in Teva’s ANDA
product is not absorbed in clinically significant amounts and thus Teva’s ANDA product infringes
claim 29.
44
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 46 of 58 PageID #: 8199
2.
Claim 30
The only dispute about infringement of claim 30 is whether Teva’s proposed ANDA
product satisfies “having an iron release rate of below 2.5% w/w.” (FF ¶ 63). The Court construed
this limitation to mean “the iron release measured in water at a pH of 3 according to European
Pharmacopeia chapter 2.9.3 using standard dissolution equipment and parameters as described in
the monograph, where iron content is analyzed by titration after 2 hours, wherein the quantity of
iron dissolved after 2 hours is less than 2.5%.” (FF ¶ 64).
At trial, one witness testified regarding infringement of claim 30 – Plaintiffs’ expert,
Dr. Myers, who tested six tablets in accordance with EP 2.9.3 using standard parameters and
dissolution equipment (Apparatus II). (FF ¶ 66). When he measured the iron content at a pH of 3
after 2 hours by titration, the iron release rate was measured at a pH that ranged from 3.22 to 3.28
across the six tablets of Teva’s ANDA product, with an average pH of 3.25. (FF ¶ 79). Dr. Myers’s
tests showed that the six tablets of Teva’s ANDA product had an average iron release rate of 1.94%
w/w, and ranged from 1.51 to 2.35% w/w. (Id.). Based on these test results, Dr. Myers concluded
that Teva’s ANDA product has “an iron release rate of below 2.5% w/w.” (FF ¶¶ 79).
Teva contests Dr. Myers’s results on two grounds: (1) that the final pH values that
Dr. Myers observed after two hours, 3.22 to 3.29 with an average of 3.25, are not “pH 3” as
required by the Court’s construction and (2) that Dr. Myers never tested Teva’s product at a starting
pH of 3 because he adjusted the pH to 2.31 prior to adding the ANDA product tablets to the test
medium. The Court addresses the arguments in turn.
a.
Final pH values
Dr. Myers’s tests of the ANDA product showed an average pH at the two hour time point
of 3.25. (FF ¶ 79). Teva argues that this does not meet the “pH of 3” required by the Court’s
45
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 47 of 58 PageID #: 8200
construction because the Court’s construction requires a pH of 3.0. 16 Federal Circuit case law,
however, warns against interpreting “endpoints of the claimed range with greater precision than
the claim language warrants.” U.S. Philips Corp. v. Iwasaki Elec. Co. Ltd, 505 F.3d 1371, 1377
(Fed. Cir. 2007). In U.S. Philips, the Federal Circuit affirmed the district court’s determination
that the claim term “between 10–6 and 10–4 μmol/mm3” means “between 1 x 10–6 and 1 x 10–4
μmol/mm3” and rejected the accused infringer’s construction of the term to mean “between 1.0 x
10–6 and 1.0 x 10–4 μmol/mm3,” noting that the specification did not intend for the quantities to be
more precise. U.S. Philips, 505 F.3d at 1378.
That is the case here. Dr. Myers explained that a POSA reading the Court’s construction
and the ’251 patent specification would understand that the target pH is specified to the whole
number – “at a pH of 3” – not a number with additional significant figures such as “3.0.” (FF ¶¶ 69,
70). 17 He explained that there is a scientific reason to specify a pH of “3” rather than 3.0, and that
is because pH 3 simulates the fed state of the stomach, 18 which a POSA would know is almost
never at a pH of exactly 3.0. (FF ¶ 70).
Moreover, Dr. Myers testified that, based on the level of precision specified in the Court’s
construction and the ’251 patent specification, “at a pH of 3” comprises a pH range of between 2.5
to 3.4 using basic rounding. (FF ¶ 69). He noted that if greater precision were required, a POSA
16
As Vifor points out, “attorney argument is not evidence and cannot rebut other admitted
evidence.” (D.I. 297 at 9 (citing Elbit Sys. of Am., LLC v. Thales Visionix, Inc., 881 F.3d
1354, 1359 (Fed. Cir. 2018) and Wasica Fin. GmbH v. Cont’l Auto. Sys., Inc., 853 F.3d
1272, 1284 (Fed. Cir. 2017))).
17
As noted above (n.7), Dr. Myers is a POSA and thus the Court recognizes his testimony as
to his interpretation as relevant to a POSA.
18
The Court notes that this testimony is consistent with Teva documents, which refer to the
fed state pH as the “most relevant” in connection with its testing of iron release.
(E.g. DTX-172 at 22).
46
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 48 of 58 PageID #: 8201
would expect to see additional significant figures explicitly stated – i.e., “3.0,” not “3.” (FF ¶ 69).
Dr. Myers’s analysis regarding rounding is also consistent with Federal Circuit case law. In San
Huan New Materials High Tech, Inc. v. Int’l Trade Comm’n, 161 F.3d 1347, 1361 (Fed. Cir. 1998),
the asserted claim recited a range of 30% to 36% of chemical compound, TRE, and the accused
product had up to 36.45% TRE.
The Federal Circuit affirmed a finding of infringement,
concluding that the number “36” was interpreted to encompass up the nearest whole number, i.e.,
up to 36.5 rather than 36.0. Id. The Federal Circuit concluded that “[i]t was not shown to be error,
legal or scientific, for the Commission to recognize these limits of accuracy, and to round the
measured weight percentages to the nearest integer.” Id.
Therefore, Dr. Myers’s opinion that his observed pH range of 3.22 to 3.28 was “at a pH of
3” to the whole number is consistent with the Court’s claim construction based on mathematical
rounding principles, and it is supported by his unrebutted testimony regarding the purpose of the
iron release test within the framework of the relevant art. Both the specification and the Court’s
construction are at the same level of precision and the Court has been given no reason to read a
greater level of precision into either Judge Stark’s construction or the description of the iron release
testing in the specification. Had the patentee or the Court wanted to specify a pH of 3.0, it could
have done so. It did not.
Teva’s arguments citing two of Plaintiffs’ confidential FDA submissions, PTX-323 and
DTX-69, do not undermine Dr. Myers’s opinions. These documents describe a particular iron
release test protocol and require that the pH at two hours be “pH 3.0 ± 0.1,” a more precise range
than required by the ’251 patent and the Court’s construction. (FF ¶¶ 82-83). Moreover, the iron
release test described in those documents is “not the same test method” as that described in the
’251 patent. (FF ¶¶ 80-86). Because the iron release tests in the FDA submissions are not the
47
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 49 of 58 PageID #: 8202
same as the iron release test described in the patent, neither of these documents informs a POSA
how to perform the iron release test detailed in the ’251 patent.
b.
Initial pH Adjustment
Teva criticizes Dr. Myers for adjusting the pH of the media to 2.31 prior to adding the
tablet samples. Dr. Myers explained, however, that EP 2.9.3 is a dissolution test but, before
dissolution began, disintegration of the tablets occurred and that affected the pH of the media.
(FF ¶ 72). To account for this, Dr. Myers adjusted the pH prior to the addition of tablets so that
the pH with tablets would be 3 during dissolution and when iron release was measured as required.
(FF ¶¶ 73-74). Neither the specification nor the Court’s construction requires the pH of the media
to be any specific value prior to tablets being placed in the media and iron release measurement.
(FF ¶ 75). Thus, Dr. Myers’s adjustment of the pH of the media prior to tablet disintegration
complied with the Court’s claim construction and, in fact, ensured that the dissolution test would
be conducted “at a pH of 3.”
Dr. Myers’s testing established that Teva’s ANDA Product has an iron release rate below
2.5%, which is in accordance with the Court’s claim construction order and the ’251 patent
specification. Therefore, Teva’s ANDA Product infringes claim 30.
B.
Validity
1.
Obviousness
a.
The ’442 Patent Does Not Render The Asserted Claims Obvious
Each of the asserted claims requires a “pharmaceutical composition” with “at least 500
mg” of iron oxy-hydroxide “per dosage form.” (FF ¶ 127). Defendant failed to prove by clear and
convincing evidence that the claimed “dosage form” of “at least 500 mg” would have been obvious
to a POSA at the time of the invention in view of the ’442 patent.
48
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 50 of 58 PageID #: 8203
The ’442 patent generally teaches that a “daily dose of the absorbents according to the
invention is, for example, 1 to 3 g, preferably about 1.5 g of iron.” (JTX-3 at 3:19-21; FF ¶¶ 132133). The ’442 patent does not teach how the daily dose would be administered (i.e., as a single
dosage form or across multiple dosage forms) or whether the daily dose would be different for the
phosphate binders provided in the examples of the ’442 patent. (FF ¶¶ 93-105, 137-140). Even
so, Defendant argues that a POSA would have understood that the 1.5 g daily dose of iron would
be administered as three individual doses comprising 500 mg of iron because this is “clearly
established” by the teachings of the ’442 patent and the POSA’s “general knowledge” regarding
the administration of phosphate binders. (D.I. 299 at 3-4, 4 (citing product labels of different
phosphate binders that are administered three times per day)). The Court disagrees. A POSA
would not have understood that the ’442 patent’s teachings of a “daily dose of . . . 1.5 g of iron”
would be split into three 500 mg doses because the ’442 patent provides no teaching about the
number of administrations per day for the daily dose. (FF ¶¶ 129-140). Further, Defendant’s
evidence of a POSA’s “general knowledge” regarding the administration of phosphate binders is
neither clear nor convincing and is outweighed by Plaintiff’s competing evidence that not all
phosphate binders are administered three times per day. (FF ¶¶ 141-142); see also Arendi S.A.R.L.
v. Apple Inc., 832 F.3d 1355, 1362 (Fed. Cir. 2016) (“[O]ur cases repeatedly warn that references
to ‘common sense’ – whether to supply a motivation to combine or a missing limitation – cannot
be used as a wholesale substitute for reasoned analysis and evidentiary support, especially when
dealing with a limitation missing from the prior art references specified.”).
Even if the Court were convinced that a POSA would have understood that the
’442 patent’s “daily dose of . . . 1.5 g of iron” would be administered as three 500 mg doses,
Defendant still must show by clear and convincing evidence that each 500 mg dose would be
49
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 51 of 58 PageID #: 8204
packaged in a single “dosage form.” Defendant argues that packaging each 500 mg dose in a
single dosage form would have been obvious to a POSA based on the ’442 patent’s general
teaching that dosages “can” be formulated for oral application as “tablets . . . or contained in
sachets, for example” and the POSA’s motivation, consistent with their “general knowledge,” to
“reduce patients’ pill burden[.]” (D.I. 299 at 4-5). The Court is not persuaded. Contrary to
Defendant’s assertion, a POSA would not have understood the ’442 patent to teach that 500 mg of
iron would be packaged in a single dosage form. (FF ¶¶ 137, 143). Instead, the ’442 patent
provides no information regarding how much iron can be loaded in each dosage form. (Id.). And
Defendant’s reliance on a POSA’s “general knowledge” to “reduce pill burden” is unconvincing
and undermined by Plaintiff’s evidence that other phosphate binders were administered across
multiple dosage forms. (FF ¶ 142; see also FF ¶¶ 145-147); see also Cardiac Pacemakers, Inc. v.
St. Jude. Med., Inc., 381 F.3d 1371, 1377 (Fed. Cir. 2004) (“Recognition of a need does not render
obvious the achievement that meets that need.”).
As is often the case, this obviousness issue comes down to weighing competing facts –
particularly competing expert testimony – regarding what a POSA would have found obvious at
the time of the invention. Here, in considering and weighing the evidence presented at trial, the
Court generally found Plaintiff’s experts to be more credible. Moreover, Defendant’s obviousness
arguments rely on taking broad teachings from the ’442 patent, then extrapolating onto them
additional limitations based on what a POSA allegedly would have known or done. As such,
Defendant’s arguments suffer from significant and improper hindsight bias. See Ortho-McNeil
Pharm., Inc. v. Mylan Lab’y, Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008) (“Mylan’s expert, . . .
simply retraced the path of the inventor with hindsight, discounted the number and complexity of
the alternatives, and concluded that the invention of topiramate was obvious. Of course, this
50
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 52 of 58 PageID #: 8205
reasoning is always inappropriate for an obviousness test based on the language of Title 35 that
requires the analysis to examine ‘the subject matter as a whole’ to ascertain if it ‘would have been
obvious at the time the invention was made.’” (emphasis in original) (citation omitted)). Thus,
the Court finds that Defendant has not shown by clear and convincing evidence that the claimed
compositions “wherein the amount of iron oxy-hydroxide per dosage form is at least 500 mg” were
obvious based on the ’442 patent alone. (FF ¶¶ 144-145). Because the “wherein the amount of
iron oxy-hydroxide per dosage form is at least 500 mg” limitation is present in each of the asserted
claims, the Court need not consider Defendant’s other arguments regarding the obviousness of the
asserted claims in view of the ’442 patent alone.
b.
The Asserted Claims are Not Obvious in View of the ’442 Patent
in Combination with Hergesell and the Other Prior Art
Asserted.
Defendant also argues that the ’442 patent in combination with Hergesell and other prior
art render the asserted claims obvious. (D.I. 299 at 12-19).
First, in addition to referring to the teachings of the ’442 patent discussed above, Defendant
argues that Hergesell “confirmed the general practice of administering phosphate binder 3 times
per day ‘with meals[.]’” (D.I. 299 at 13; JTX-7 at 2 (“[P]atients were subsequently given a constant
dose of 3 x 2.5 g stabilized polynuclear iron hydroxide . . . provided as a powder in preweighed
sachets. The material was suspended in water and ingested together with meals.”)). The Court is
not convinced by Defendant’s argument. Foremost, Hergesell does not refer to iron oxy-hydroxide
formulations comprising saccharose. (FF ¶¶ 108-116, 154-156). This is important because iron
oxy-hydroxide formulations comprising saccharose are required by the asserted claims and are
what is taught by the ’442 patent in Example 1, which Defendant relies on. (FF ¶¶ 150-157). Thus,
because Hergesell’s formulations are different than the formulation described in Example 1 of the
51
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 53 of 58 PageID #: 8206
’442 patent, a POSA would not look to the teachings of Hergesell regarding dosages in their
obviousness analysis of Example 1 of the ’442 patent. (FF ¶¶ 150-158).
Even if the Court were convinced that, based on the teachings of the ’442 patent and
Hergesell, a POSA would have understood that the ’442 patent’s “daily dose of . . . 1.5 g of iron”
should be split into three 500 mg doses, Defendant still must prove that each 500 mg dose would
be packaged as a single “dosage form.” In this regard, Defendant argues, in addition to the
teachings of the ’442 patent alone discussed above, that the ’442 patent in combination with
teachings of the ’079 patent or Hergesell teach a single 500 mg dosage form. (D.I. 299 at 12-13).
Regarding the ’079 patent, Defendant argues that the “[t]he backdrop of those teachings of
the ’442 Patent was the earlier [U.S. Patent No. 4,970,079 patent (“the ’079 Patent”)], which [a
POSA would have understood to have] already disclosed and suggested a ‘unitary solid dosage
form such as a compressed tablet’ containing ‘500 mg or more’ of iron oxy-hydroxide in ‘each
oral dose.’” (D.I. 299 at 12-13 (citing ’079 Patent at 3:36-55 (“[T]he oxy-iron compound can be
formulated as a liquid or gel suspension, or in a unitary solid dosage form such as a compressed
tablet or capsule. . . . Thus, each oral dose of the therapeutic oxy-iron containing composition in
accordance with this invention can contain from about 50 mg to about 500 mg or more of oxy-iron
compound.”))). Again, however, the Court is not convinced in this regard. The ’079 patent
broadly describes “oxy-iron compounds,” including at least iron oxides, iron hydroxide and iron
oxyhydroxides. (FF ¶¶ 119-126; 160; ’079 Patent at 3:12-63). The ’079 patent then teaches a
dosage of an oxy-iron “composition in accordance with this invention can contain from about
50 mg to about 500 mg or more of oxy-iron compound,” where this teaching is not specific to
which of the species of oxy-iron compounds may fall into different portions of that range. (’079
Patent at 3:52-55). Additionally, when considering the ’079 patent’s teachings, a POSA would
52
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 54 of 58 PageID #: 8207
recognize that the ’079 Patent does not describe any finished dosage formulations or how to
formulate the disclosed oxy iron compounds. (FF ¶ 171). Moreover, the ’079 patent teaches that
a relatively smaller 174 mg dosage of one iron oxide compounds (ferrihydrite) was effective.
(FF ¶¶ 123-125, 161-162). Thus, the Court finds that Defendant has not shown by clear and
convincing evidence that a POSA would combine the teachings of the ’442 patent and ’079 patent
to formulate a 500 mg, single dosage form. Indeed, the ’079 patent’s broad teaching directed to
the genus of oxy-iron compounds cannot be assumed to apply to all species for this obviousness
analysis. See In re Baird, 16 F.3d 380, 382 (Fed. Cir. 1994) (“The fact that a claimed compound
may be encompassed by a disclosed generic formula does not by itself render that compound
obvious.”); In re Jones, 958 F.2d 347 (Fed. Cir. 1992) (“declin[ing] to extract from [the case law]
the rule that . . . regardless of how broad, a disclosure of a chemical genus renders obvious any
species that happens to fall within it.”).
Regarding Hergesell, Defendant argues that “Hergesell confirmed [providing the
phosphate binder] with a high load of iron oxy-hydroxide in a single dosage form (i.e., a sachet
powder packet) containing approximately 800 mg of iron oxy-hydroxide.” (D.I. 299 at 13). The
Court disagrees. First, as explained above, Hergesell’s teachings regarding the dosages are not
applicable to Example 1 of the ’442 patent. (See FF ¶¶ 108-116, 150-158). Even so, Hergesell
only teaches “a constant dose of 3 x 2.5 g stabilized polynuclear iron hydroxide . . . provided as a
powder in preweighed sachets.” (Hergesell at 2; FF ¶ 163). From this, a POSA would not
understand how much powder is contained in each sachet (i.e., 10 sachets including 250 mg with
each 2.5 g dose, or one sachet containing 2.5 g) or how much iron oxyhydroxide would be included
per 2.5 g. (FF ¶ 163). Because of this, the Court finds that Defendant has not shown by clear and
53
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 55 of 58 PageID #: 8208
convincing evidence that a POSA would combine the teachings of the ’442 patent and Hergesell
to formulate a 500 mg, single dosage form.
Thus, having considered and rejected each of Defendant’s arguments that the “dosage
form” of “at least 500 mg” limitation is obvious (the ’442 patent alone and the ’442 patent in
addition to other prior art), the Court finds that the Defendant has not shown by clear and
convincing evidence that the claimed compositions “wherein the amount of iron oxy-hydroxide
per dosage form is at least 500 mg” were obvious. Because the “wherein the amount of iron oxyhydroxide per dosage form is at least 500 mg” limitation is present in each of the asserted claims,
the Court need not consider the Defendant’s other arguments regarding the obviousness of the
asserted claims.
c.
Objective Indicia
Plaintiff has asserted that several objective indicia of non-obviousness, long-felt but unmet
need, unexpected results, and commercial success further support that the asserted claims are not
obvious. As discussed above (FF ¶¶ 164-184), the Court has found that Velphoro satisfied a longfelt but unmet need and has enjoyed some measure of commercial success, both of which provide
further support the finding of non-obviousness. Having found that Defendant failed to establish a
prima facie case of obviousness for the asserted claims, however, the Court, does not address that
evidence again in detail here.
2.
Enablement
As a preliminary matter, Defendant argues that claims 29 and 30 “broadly claim functional
properties without any formulation-limiting details” and, according to the Federal Circuit’s ruling
in Amgen, this “weighs heavily against enablement.” (D.I. 299 at 28-29 (citing Amgen Inc. v.
Sanofi, 987 F.3d 1080 (Fed. Cir. 2021))). The Court, however, disagrees that claims 29 and 30
54
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 56 of 58 PageID #: 8209
lack “any formulation-limiting details.” Instead, claims 29 and 30, which depend on claim 1, set
forth a specific “pharmaceutical composition comprising . . . iron oxy-hydroxide in high loading
. . . and . . . carbohydrates comprising saccharose and starch . . . wherein the amount of iron oxyhydroxide per dosage form is at least 500 mg.” (JTX-1 at 15:23-31). These formulation-limiting
details must be considered in an enablement analysis.
a.
Claim 29
Regarding claim 29, Defendant argues that a POSA would not be able to determine what
level of iron absorption is “clinically significant.” (D.I. 299 at 29-30). In construing the claims,
however, Judge Stark concluded that “[b]ased on the description in the specification, a POSA
would know the bounds of the claim term with reasonable certainty” because even though “the
claim does not set forth a specific amount of iron oxy-hydroxide that may be absorbed, a POSA
would know that any absorption would be minimal and unintentional compared to the absorption
of iron deficiency treatments.” (D.I. 114 at 6). Consistent with this, Dr. Rastogi explained that
clinical significance would be readily understood by a healthcare provider, and he gave several
examples of drugs that both do and do not release clinically significant amounts of iron.
(FF ¶¶ 186-187). Here, to make and use the claimed invention, a POSA could follow the working
examples, which the ’251 patent states are “essentially non-bioabsorbable.” (FF ¶¶ 190-191).
Teva also argues that claim 29 requires undue experimentation because a POSA would
have to test “each and every individual patient” to “determine whether a particular product, when
administered to a particular patient, would satisfy the claimed function.” (D.I. 299 at 29-30). The
Court, however, credits Dr. Rastogi’s testimony that this is not how a POSA would understand
“clinical significance,” which is determined by looking at patient population averages, not any
individual outcomes. (FF ¶ 189).
55
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 57 of 58 PageID #: 8210
For these reasons, the Court finds that Defendant failed to prove by clear and convincing
evidence that claim 29 is invalid for lack of enablement.
b.
Claim 30
With respect to claim 30, Defendant argues that undue experimentation is required to
achieve the claimed release rate based on “Plaintiffs’ argument that the brand of starch may impact
the release rate.” (D.I. 299 at 30). In making this argument, however, Defendant ignores that the
’251 patent identifies a specific brand of starch that can be used to make formulations with an iron
release rate below 2.5%. (FF ¶ 196). Moreover, Teva misconstrues the law of enablement. Under
Teva’s logic, Plaintiffs need to enable every potential combination and brand of starch. But
enablement requires only a sufficient disclosure that would allow a POSA to practice the claim
invention. See Invitrogen Corp. v. Clontech Labs., Inc., 429 F.3d 1052, 1071 (Fed. Cir. 2005)
(“The enablement requirement is met if the description enables any mode of making and using the
invention.” (citation omitted)). Here, the ’251 patent gives explicit guidance how to make the
claimed pharmaceutical composition, including information about the type and brand of starch that
can be used to achieve the claimed iron release rate. (FF ¶¶ 194-196). Nothing more is necessary.
For these reasons, the Court finds that Defendant failed to prove by clear and convincing
evidence that Claim 30 is invalid for lack of enablement.
IV.
CONCLUSION
As discussed herein, after considering the entire record and the applicable law, the Court
concludes that (1) Teva’s ANDA product infringes claims 33 and 56 of the ’251 patent; (2) Vifor
has proved that Teva’s ANDA product infringes claims 29 and 30 of the ’251 patent; (3) Teva has
failed to prove that any of claims 29, 30, 33, and 56 of the ’251 patent are invalid for obviousness
56
Case 1:18-cv-00390-MN Document 325 Filed 08/18/22 Page 58 of 58 PageID #: 8211
and; (4) Teva has failed to prove that either of claims 29 and 30 is invalid for lack of enablement.
An appropriate order will be entered.
57
Disclaimer: Justia Dockets & Filings provides public litigation records from the federal appellate and district courts. These filings and docket sheets should not be considered findings of fact or liability, nor do they necessarily reflect the view of Justia.
Why Is My Information Online?