AstraZeneca AB v. Zydus Pharmaceuticals (USA) Inc.

Filing 170

TRIAL OPINION: I find that Zydus has failed to prove any of the asserted claims are obvious. As Zydus raises no other invalidity theories, I find each of the asserted claims infringed. The parties shall submit a final judgment consistent with this memorandum opinion within one week. Signed by Judge Richard G. Andrews on 10/15/2021. (nms)

Case 1:18-cv-00664-RGA Document 170 Filed 10/15/21 Page 1 of 10 PageID #: 5181

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
ASTRAZENECA AB,
Plaintiff;
V.

Civil Action No. 18-664-RGA

ZYDUS PHARMACEUTICALS (USA) INC .,
Defendant.

TRIAL OPINION
Michael P. Kelly, Daniel M. Silver, Alexander M . Joyce, MCCARTER & ENGLISH LLP,
Wilmington, DE; Charles E. Lipsey, Ryan P. O' Quinn, FINNEGAN, HENDERSON,
F ARABOW, GARRETT & DUNNER LLP, Reston, VA; Jill K. MacAlpine, Matthew Hlinka,
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER LLP, Washington, D.C.;
John D. Livingstone, M. David Weingarten, Megan L. Meyers, FINNEGAN, HENDERSON,
FARABOW, GARRETT & DUNNERLLP, Atlanta, GA.
Attorneys for Plaintiff.
John C. Phillips, Jr., Megan C. Haney, PHILLIPS MCLAUGHLIN & HALL, P.A. , Wilmington,
DE; Michael J. Gaertner, Myoka Kim Goodin, Jennifer M. Coronel, Christopher J. Cassella,
LOCKE LORD LLP, Chicago, IL; Alan B. Clement, Zhibin Li, LOCKE LORD LLP, New York,
NY.
Attorneys for Defendant.

October

If , 2021

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On May 1, 2018, AstraZeneca AB brought this action against Zydus Pharmaceuticals,
Inc. for infringement of U.S . Patent Nos. 6,414,126 ("the ' 126 patent") and 6,515,117 ("the ' 117
patent") under 35 U.S.C. § 271(e)(2)(A). (D.I. 1). I held a four-day bench trial. (D.I. 152-155). 1
By trial, the parties had narrowed the dispute to the validity of claims 1-3, 14, and 16 of the ' 117
patent. (D.I. 135, ,rs ; Tr. at 2:22-3:1; see D.I. 66 at 2).
Before me is the issue of the validity of the asserted claims. Zydus argues that each of
the asserted claims is invalid for obviousness. (D.I. 160). I have considered the parties' post-trial
submissions. (D.I. 158, 159, 160, 161 , 163, 164).

I.

BACKGROUND
The '117 patent is directed to compounds and methods for treatment of diabetes and

related diseases through inhibition of sodium dependent glucose transporters (SGL T2) found in
the intestine and kidney. (D.I. 1-2 at 1: 10-14). AstraZeneca owns NDA No. 202293 for Farxiga
(dapagliflozin) tablets for the treatment of diabetes and related diseases. (D.I. 1 at 8). The ' 117
patent is listed in the Orange Book for Farxiga. (Id.). Zydus filed ANDA No. 211582 seeking
FDA approval for manufacture, use, and sale of a generic dapagliflozin tablet. (Id. at 6). Zydus
sent its Paragraph IV certification to AstraZeneca on March 20, 2018. (Id. at 4). AstraZeneca
then filed this action alleging infringement by Zydus ' s ANDA submission. (Id.); 35 U.S.C. §
271(e)(2)(A).

II.

ASSERTED CLAIMS
Claims 1-3 of the '11 7 patent recite a "pharmaceutical composition" and various

permutations of the composition: complexed with pharmaceutically acceptable salts,

1

I cite to the trial transcript as "Tr." The trial transcript is consecutively numbered.

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stereoisomeric compositions, or a prodrug ester. (D.I. 1-2, ' 117 patent, 25 :32-67). The core
pharmaceutical composition recited by the claims is shown below:

o......_Et

0
HO
.,,,,,

11

0H

OH
Fig. 1 - Pharmaceutical composition in Claims 1-3 of the '117 Patent (PTX0242 at 183)
Claims 14 and 16 of the ' 117 patent teach methods for treatment of diabetes and related
diseases using a "therapeutically effective amount" of the composition defined in claim 1. (Id. at
claims 14, 16). The relevant claims provide:
14. A method for treating or delaying the progression or onset of diabetes, diabetic
retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin
resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or
glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic
complications, atherosclerosis or hypertension, or for increasing high density lipoprotein
levels, which comprises administering to a mammalian species in need of treatment a
therapeutically effective amount of a compound as defined in claim 1.
16. A method for treating type II diabetes which comprises administering to a
mammalian species in need of treatment a therapeutically effective amount of a
compound as defined in claim 1 alone or in combination with another antidiabetic agent,
an agent for treating the complications of diabetes, an anti-obesity agent, an
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antihypertensive agent, an antiplatelet agent, an anti-atherosclerotic agent and/or a
hypolipidernic agent.
(PTX0242 at 26:57-67; 27:16-24).

III.

LEGAL STANDARD
A patent claim is invalid as obvious under 35 U.S.C. § 103 "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; see also KSR Int '! Co.

v. Teleflex Inc., 550 U.S. 398, 406-07 (2007). "Under§ 103, the scope and content of the prior art
are to be determined; differences between the prior art and the claims at issue are to be
ascertained; and the level of ordinary skill in the pertinent art resolved. Against this background,
the obviousness or nonobviousness of the subject matter is determined." KSR, 550 U.S. at 406
(internal citation and quotation marks omitted).
A court is required to consider secondary considerations, or objective indicia of
nonobviousness, before reaching an obviousness determination, as a "check against hindsight
bias." In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d
1063, 1078-79 (Fed. Cir. 2012). "Such secondary considerations as commercial success, long felt
but unsolved needs, failure of others, etc., might be utilized to give light to the circumstances
surrounding the origin of the subject matter sought to be patented." Graham v. John Deere Co. of

Kansas City, 383 U.S. 1, 17-18 (1966).
Zydus has the burden of proving obviousness by clear and convincing evidence.

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IV.

ANALYSIS
Zydus argues that the asserted claims are invalid as obvious. For the following reasons, I

find each asserted claim not obvious.

A.

Findings of Fact
1. A person of ordinary skill in the art is a pharmaceutical chemist with a Ph.D.
and several years of experience in research and development of new
pharmaceutical compositions, including experience in synthetic organic
chemistry and structure activity relationship (SAR) analysis. (D.I. 161, 11,
D.I. 159,122). The POSA would either have a basic knowledge of the disease
to be treated, as well as the relevant assays for evaluating a drug candidate for
that disease, or work with a medical doctor with drug development training
for that disease. (D.I. 161 , 11 , D.I. 159, 122).
2. The '117 patent has a priority date of May 20, 2002. (PTX0242 at 170).
3. Zydus ' s proffered references-WO ' 128 (DTX007), Hongu (PTX0073), and
Kees (DTX0lO)-are prior art. (D.I. 135-1, Ex. A, 1141, 46, 52).
4. WO '128 discloses eighty structurally similar compounds as prospective
SGLT2 inhibitors. (DTX007). Twenty-five of these fall within the genus
Formula IB, which the patentee designates as the " [m]ost preferred" set of
embodiments. (Id.). The Formula IB genus has preferred chemical moieties at
certain positions, as shown below in Fig. 2:

Most preferred are compounds of formula I of the
20

structure IB
IB

where R1 is hydrogen, halogen or lower alkyl and R4 is
lower alkyl, R5 aO, -OCHF2 , or -SR 5e.
25

It is preferred that

R1 be linked para to the glucoside bond and the R4
substituent be li~ked at the pa.ra position.
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Fig. 2 - WO '128 Formula IB Compounds (DTX007 at 12)
5. WO '128 does not provide data of comparative biological activity (i.e.,
SGL T2 inhibition) for any of its listed compounds, nor does it indicate why its
Formula IB compounds are preferred candidates for development.
6. Hongu teaches away from replacing the methoxy at the 4-position on the
distal ring (R4 Fig. 2) with a heavier moiety because it shows decreased
biological activity when the methoxy is replaced with larger distal alkoxy
groups. (PTX0073 at 7) ("As the alkyl or alkoxy group became larger, the
activity tended to be reduced.").
7. Kees teaches away from replacing the methoxy at the 4-position on the distal
ring with a larger alkoxy moiety because it shows decreased biological
activity for compounds with larger alkoxy groups. (DTX0l0 at Table 1). The
preferred compound in Kees is an ethyl group at the R 4 position rather than an
alkoxy. (Id at Table 2).
8. SAR analysis is an iterative approach to rational drug design used by POSAs
to optimize a potentially therapeutic molecule by evaluating whether changes
to its chemical structure affect the molecule's desired therapeutic property,
which is typically a change in biological activity. (Tr. at 264:8- 266:6). The
molecular scaffold (i.e. , the core structure) that is chosen for iterative
permutation during SAR is called the "lead compound." (D.I. 161 at ,r,r 15 ,
20-21).
9. Because WO ' 128 does not evaluate the activity of its compounds, including
those in Formula IB, it is not an SAR study. (Tr. at 307:23-308:2, 356:223 57 :21 ). WO '128 does not identify a lead compound because it did not test
for favorable activity or pharmacological characteristics that would have
identified a compound as such.
10. Based on the lack of biological activity data in WO '128 and the teaching
away from the use of larger alkoxy groups at the 4-distal position by Hongu
and Kees, a POSA would not have been motivated to swap the distal 4methoxy in WO '128 ' s Example 12 with an ethoxy (which would otherwise
yield the molecule claimed in the ' 117 patent).
11. Given the lack of available biological data for candidate SGL T2 inhibitors and
the unpredictability of changes in biological activity due to modification of
chemical structure, a POSA would not have had a basis to expect
dapagliflozin to exhibit better glucose-reducing effects than the closest prior
art, such as Example 12.

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B.

Conclusions of Law

Claims 1-3 of the ' 117 patent recite the same core chemical compound. "For a chemical
compound, a prima facie case of obviousness requires structural similarity between claimed and
prior art subject matter . . . where the prior art gives reason or motivation to make the claimed
compositions." Eli Lilly & Co. v. Zenith Goldline Pharms., Inc., 471 F.3d 1369, 1377 (Fed. Cir.
2006) (internal quotations omitted). Structural similarity between the prior art and the patented
compound is insufficient, on its own, to show motivation to combine. Takeda Chem. Indus. v.
Alphapharm Pty. , Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007) ("Thus, in cases involving new

chemical compounds, it remains necessary to identify some reason that would have led a chemist
to modify a known compound in a particular manner to establish prima facie obviousness of a
new claimed compound.").
Based on my factual findings-specifically the lack of biological data available for the
closest prior art, WO ' 128, and the teaching away of prior art from inserting an ethoxy into the 4distal position-Zydus has not presented clear and convincing evidence of obviousness.
First, Zydus argues that a POSA would have been motivated to select Example 12 of WO
'128 as a lead compound. (D.I. 160 at 4). Going through WO ' 128, Zydus identifies a number of
preferred substituents that would have found their way into the various positions required to form
Example 12. (Id. at 4-5). These include, for example, selecting a lead compound with a 4methoxy substituent because that moiety was most represented at the R4 position. (Id. at 6)
(citing D.I. 161 Finding of Fact 21 (in tum citing Tr. 93:25-94:12, 95 :8-11)). Zydus also argues
that disclosure of biological data is not required to show a POSA' s motivation to select Example
12 as a lead compound because the ' 117 patent itself does not disclose biological data to do so.
(D.I. 160 at 12).
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Zydus ' s arguments do not address, however, the premise that identification of a lead
compound requires some indication that the preferred scaffold is likely to yield a biologically
active compound upon modification. No such activity data is reported in WO ' 128 for a POSA to
make a choice of lead compound based on the contents therein. As to Zydus's argument that the
' 117 patent also does not provide any biological data, this is not an appropriate comparison
because sixteen of the patent' s seventeen claims rely on a single molecular structure. A POSA
could reasonably infer that the compound identified in claims 1-16 is the lead candidate for
further development; the same cannot be said for any one of eighty species in WO ' 128, none of
which are presented with any biological activity data. Even the Formula IB genus, which the
authors of WO ' 128 designate their "[m]ost preferred" group, has twenty-five members. Without
additional data to differentiate between the species in Formula IB, a POSA would not have
known which structure to choose as a lead compound.
Second, Zydus argues the "one small, conservative change" from a methoxy to an ethoxy
at the 4-distal position that is required to go from Example 12 of WO ' 128 to dapagliflozin
would have been obvious to a POSA. (Id. at 7). Specifically, it argues that upon selection of the
lead compound, a POSA would naturally seek to make a spectrum of small changes, which
would include "the common replacement of methoxy with ethoxy." (Id. at 8-9) (citing Tr.
99:22-100: 19). Because the change is small and in the normal course of a POSA' s conduct of
SAR, Zydus argues that there would be a reasonable expectation of success. (Id. at 9).
Zydus' s argument presupposes that a POSA would have been able to identify Example
12 as the appropriate lead compound, which I have already noted I do not think is the case. Even
supposing it were, however, I do not think Zydus has shown clear and convincing evidence that a
POSA would have been motivated to make the required change from a methoxy to an ethoxy at
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the R4 position. Neither Hongu nor Kees supports the shift from methoxy to ethoxy. Moreover,
Dr. Gribble's testimony that a POSA would have made the required change in due course "as
part of the iterative process of SAR" seems to have some hindsight bias. (Tr. at 100: 15-19). On
the other hand, I find credible Dr. Batchelor' s testimony that a POSA would not have
automatically considered making the required change because none of the eighty compounds
shown in WO '128 had an ethoxy at the R 4 position. (Tr. at 317:9-25).
Third, Zydus argues that the prior art does not teach away from substitution of the ethoxy
at the R4 position. (D.I. 160 at 10-11). Pointing to Hongu and Kees, Zydus argues that neither
reference clearly teaches that a larger alkoxy group is likely to produce less favorable results.

(Id.) . Dr. Batchelor's testimony, Defendant argues, conceded, "Hongu alone may not be
sufficient to teach a POSA away from larger alkyl groups." (Id. at 11) (citing Tr. at 385:1-23).
I have already found that both Hongu and Kees teach away from substitution of the
ethoxy for the methoxy at the R4 position because Hongu disfavors larger alkoxy groups at that
position and Kees presents an ethyl group, which is not an alkoxy, as its most preferred group.
Even were that not the case, Zydus's arguments misconstrue its burden of proof. It is not
sufficient for Zydus to show that Hongu and Kees did not teach away from making the necessary
modification to render dapagliflozin obvious; Zydus needed to show by clear and convincing
evidence that a POSA would have had an affirmative reason to make that change. No such
reason was given.
I therefore find that Zydus has not shown by clear and convincing evidence that claims
1-3 of the '117 patent are invalid as obvious. Because method claims 14 and 16 rely on the same
chemical compound as claims 1-3, dapagliflozin, and both parties' arguments for those method

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claims on their analysis of the obviousness of the dapagliflozin (D.I. 160 at 1; D.I. 158 at 18), I
also find claims 14 and 16 of the ' 117 patent not obvious.
The parties dispute various purported secondary considerations of non-obviousness,
primarily "unexpected results." (D.I. 158 at 28-37; D.I. 160 at 13-19). The disputed secondary
considerations cannot help Zydus. Because Zydus has not made the case for obviousness by
clear and convincing evidence (without consideration of the disputed factors), I do not need to
consider them, and I therefore do not reach them.

V.

CONCLUSION
For the foregoing reasons, I find that Zydus has failed to prove any of the asserted claims

are obvious. As Zydus raises no other invalidity theories, I find each of the asserted claims
infringed. (D.I. 135-1 , Ex. A, ~ 38).
The parties shall submit a final judgment consistent with this memorandum opinion
within one week.

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