John E. Flaherty 

Jonathan M.H. Short 

McCARTER & ENGLISH, LLP 

Four Gateway Center 

100 Mulberry Street 

Newark, New Jersey 07102 

(973) 622-4444 

Attorneys for Plaintiffs/Counterclaim-Defendants 

AstraZeneca AB, Aktiebolaget Hässle, 

AstraZeneca LP, KBI Inc. and KBI-E Inc. 

Of Counsel: 

Henry J. Renk 

Bruce C. Haas 

Colleen Tracy 

Joshua I. Rothman 

FITZPATRICK, CELLA, HARPER 

 & SCINTO 

1290 Avenue of the Americas 

New York, New York 10104-3800 

(212) 218-2100 

Einar Stole 

COVINGTON & BURLING LLP 

1201 Pennsylvania Avenue, NW 

Washington, DC 20004-2401 

(202) 662-6000 

UNITED STATES DISTRICT COURT 

FOR THE DISTRICT OF NEW JERSEY 

ASTRAZENECA AB; AKTIEBOLAGET 

HÄSSLE; ASTRAZENECA LP; KBI INC.; 

and KBI-E INC., 

Plaintiffs and 

Counterclaim-Defendants,

 v. 

HANMI USA, INC., HANMI 

PHARMACEUTICAL CO., LTD., HANMI 

FINE CHEMICAL CO., LTD, and HANMI 

HOLDINGS CO., LTD., 

 

Defendants and 

Counterclaim-Plaintiffs. 

Civil Action No. 3:11-CV-00760-JAP-TJB 

Judge Joel A. Pisano 

Magistrate Judge Tonianne J. Bongiovanni 

ATTORNEY CONFIDENTIAL 

PURSUANT TO PROTECTIVE ORDER 

FILED UNDER SEAL 

ASTRAZENECA’S REPLY MARKMAN BRIEF 

Case 3:11-cv-00760-JAP-TJB Document 212 Filed 04/10/12 Page 1 of 10 PageID: 8628
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Pursuant to the Court’s March 1, 2012 Letter Order (D.I. 206), AstraZeneca 

submits this reply brief in response to newly disclosed positions and evidence presented in 

Hanmi’s responsive Markman submissions. 

Hanmi asserts that AstraZeneca’s construction of the ’504 patent claim term, 

“alkaline salt” of esomeprazole, includes toxic salts. In asserting this new position, Hanmi takes 

out of context certain statements made by AstraZeneca and AstraZeneca’s expert, Dr. Davies. 

As explained below, consideration of these statements in their proper context makes clear that 

AstraZeneca has never taken a position that toxic salts are among the salts in the ’504 patent 

claims. In fact, the parties are in agreement that such a construction would be inconsistent with 

the understanding of a person of ordinary skill in the art. 

Hanmi also newly asserts that a person of ordinary skill would expect 

esomeprazole to be compatible with acidic conditions and thus would not exclude acid addition 

salts from the scope of the ’192 patent claim term, “pharmaceutically acceptable salt” of 

esomeprazole. However, for support, Hanmi points only to prior art patents that are silent as to 

the stability of omeprazole (or its enantiomers) under acidic conditions, and that do not 

exemplify any acid addition salts of omeprazole (or its enantiomers). In selecting this art, Hanmi 

has also ignored clear statements in prior art previously cited by both parties that would have led 

a person of ordinary skill to conclude that esomeprazole is incompatible with acidic conditions. 

Hanmi’s new positions are therefore without merit.1

 

 

1

 References are provided herein to AstraZeneca’s opening Markman brief (“AZ Br.”; D.I. 

133.0), Hanmi’s responsive Markman brief (“Hanmi R. Br.”; D.I. 174.0), Patrick L. 

Chen’s Nov. 7, 2011 declaration (“Chen”; D.I. 133.1-2), Michael E. Furrow’s Jan. 6, 

2012 declaration (“Furrow”; D.I. 176.1-3, 177.0-3); Renita S. Rathinam’s Jan. 6, 2012 

declaration (“Rathinam”; D.I. 175.0-5, 179.0-10); Dr. Stephen G. Davies’ Nov. 7, 2011 

declaration (“Davies”; D.I. 133.3-5), Dr. Jerry L. Atwood’s Jan. 6, 2012 supplemental 

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I. AstraZeneca’s Proposed Construction of “Alkaline Salt” of Esomeprazole in ’504 

Patent Claims 1, 2, 4, 6 and 7 Does Not Embrace Toxic Salts 

AstraZeneca’s proposed construction for “alkaline salt” of esomeprazole in the 

claims of the ’504 patent is “a basic salt (here, a salt in which (–)-omeprazole is negatively 

charged) that is suitable for use in a pharmaceutical formulation.” (Emphasis added.) For 

support, AstraZeneca has cited, inter alia, the ’504 patent claims, which are directed to 

pharmaceutical formulations and methods of treatment, as well as the ’504 patent specification, 

from which the medical utility is clear. (AZ Br. 17–18). See, e.g., Phillips v. AWH Corp., 415 

F.3d 1303, 1312–13 (Fed. Cir. 2005) (a claim term is to be construed “in the context of the 

particular claim in which the disputed term appears, [and] the entire patent”). From the proposed 

construction, and the pharmaceutical context provided by the claims and specification 

specifically called out by AstraZeneca, it should be clear that AstraZeneca did not propose that 

the claimed “alkaline salts” of esomeprazole include toxic salts—such a construction would be 

unreasonable. See, e.g., Mitsubishi Chem. Corp. v. Barr Labs., Inc., 435 Fed.Appx. 927, 934–35 

(Fed. Cir. 2011) (In “[c]laims to ‘pharmaceutical compositions’ . . . [e]ach of the constituent 

parts of the composition must be pharmaceutically acceptable . . . .”). 

Nevertheless, Hanmi, in its responsive Markman brief and accompanying 

supplemental declaration of Dr. Atwood, asserts that AstraZeneca’s construction embraces toxic 

salts, and offers new evidence ostensibly to rebut that construction. Hanmi’s misunderstanding 

appears to be the result of reading certain statements made by AstraZeneca and its chemistry 

expert, Dr. Davies, out of context. 

 

declaration (“Atwood Supp.”; D.I. 174.1); and to the supplemental declaration of Dr. 

Stephen G. Davies submitted herewith (“Davies Supp.”). 

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In AstraZeneca’s opening Markman brief, AstraZeneca explained that an 

“alkaline salt,” as a general concept, is simply a “basic salt”—“alkaline” meaning “basic.” This 

was provided as background, and was supported by the testimony of Dr. Davies and a page from 

a contemporaneous dictionary that included definitions of “alkali metals” and “alkaline earth 

metals” (which generate basic solutions in water), and “alkalinity” and “alkaline solution” 

(which simply require that the solution in question be basic). However, each general explanation 

was followed by a clarification that given the pharmaceutical context provided by the claims and 

the specification of the ’504 patent, only pharmaceutically acceptable alkaline salts of 

esomeprazole are covered by the claims. (AZ Br. 7–8; Davies ¶¶ 36, 41, 51, Exh. 2; Davies 

Supp. ¶¶ 3–16). 

Dr. Davies reemphasized the importance of the context provided by the ’504 

patent to the construction of “alkaline salt” at his deposition: 

Q: But in no claim is the alkaline salt described as ‘pharmaceutical’ or 

‘pharmaceutically acceptable[,]’ [i]s that correct? 

A: Well, it would have to be—or else it wouldn’t be in a pharmaceutical 

formulation.” 

(Furrow Exh. 1 at 64:3–8). Hanmi ignores this evidence when it misinterprets a subsequent 

statement by Dr. Davies that “all alkaline salts fulfill the criteria covered by the patent” as 

indicating that AstraZeneca’s construction embraces toxic salts. But, not only did Dr. Davies 

explain his position earlier in his deposition, he also made clear, in response to the question 

immediately following the answer that Hanmi relies on, that salts of esomeprazole are covered 

by the claims only “if they fulfill the other—all the other criteria of the ’504 patent.” (Id. at 

172:18–22; see also 173:21–24). And, the subsequent question reveals that, at least at the time 

of the deposition, Hanmi fully understood AstraZeneca’s and Dr. Davies’ position that the 

claimed salts were pharmaceutically acceptable: 

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Q: Would a person of skill in the art understand that the titanium salt of the (–)-

enantiomer of omeprazole would have properties sufficient to make it 

pharmaceutically acceptable, as you’ve explained is part of the ’504 patent 

claims? 

(Id. at 172:23 to 173:2). Dr. Davies has responded to Hanmi’s misinterpretation of his testimony 

in his supplemental declaration accompanying this brief. (Davies Supp. ¶¶ 3–22). 

In light of the foregoing, Hanmi’s new evidence addresses a construction that is 

not before the Court; the Parties are in agreement that it would be unreasonable to interpret this 

claim term as covering toxic salts. (See Hanmi R. Br. 4; Atwood Supp. ¶¶ 15–23; Davies Supp. 

¶¶ 3–22). 

Given the proper understanding of AstraZeneca’s proposed construction, Hanmi’s 

newly articulated concerns about the ability of one skilled in the art to identify and prepare all 

possible alkaline salts of esomeprazole are inapposite. Indeed, as previously noted (D.I. 92.1, 

Exh. A at 1; D.I. 189 at 2; Davies ¶¶ 42 fn. 3, 54, 55), a person of ordinary skill would have been 

able to readily identify, for example, at least the six exemplary cations in the ’504 patent; the 

additional cation in prior patents directed to “alkaline salts” of omeprazole (Davies Exhs. 6 and 

7); the 21 cations known to be fit for human consumption identified in the Berge reference (D.I. 

112-4 at 2–3); and references reporting the pharmaceutical suitability of strontium salts (Davies 

Exhs. 3–5).2, And the person of ordinary skill would not consider toxic salts. The universe of 

 

2

 Hanmi now contends that the strontium references “say nothing about whether any of the 

compounds disclosed are suitable for use in a pharmaceutical formulation.” This 

assertion flies in the face of express statements in these references (see, e.g., Davies Exh. 

5 at 547: “strontium (Sr) at low dosage levels has been proposed to be of therapeutic 

value in patients with osteoporosis”), and of Hanmi’s citation of the very same references 

 to the Patent 

Office in its own patent (see D.I. 190, Exh. F at col. 2, ll. 49–52: “strontium exerts no 

safety problems even at a dose of 633/mg/kg/day in rats,” citing one of the same articles). 

(Davies Supp. ¶ 28). 

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possible salts is thus far less than the “hundreds of thousands” of salts (Atwood Supp. ¶ 12) that 

Hanmi mistakenly asserts AstraZeneca’s construction to embrace.3 (Davies Supp. ¶¶ 23–42). 

II. Hanmi’s New Evidence Does Not Rebut the Clear Statements in the Intrinsic 

Evidence and Prior Art that Would Have Led a Person of Ordinary Skill to 

Conclude that Esomeprazole Is Incompatible with Acidic Conditions 

AstraZeneca’s construction of “pharmaceutically acceptable salt” of 

esomeprazole in the method of administration claims of the ’192 patent is commensurate in 

scope with the “alkaline salt” of esomeprazole in the ’504 patent claims. For support, 

AstraZeneca has cited (D.I. 92.1, Exh. C pages 3–4; AZ Br. 17–18; Davies ¶¶ 63–67) column 1 

of the’192 patent that incorporates the “salt forms of the single enantiomers of omeprazole” from 

the ’504 patent (Chen Exh. 2, col. 1, ll. 10–13); the ’504 patent where it states that “acidic 

conditions” would be “devastating” for the individual enantiomers of omeprazole (Chen Exh. 1, 

col. 1, ll. 27–42); the declaration of Dr. Andersson from the ’504 patent file history 

characterizing the enantiomers of omeprazole as “acid labile” (Chen Exh. 4 at AZ0005000175); 

and AstraZeneca’s U.S. Patent No. 4,738,974 patent and European Patent No. 0 124 495 that 

state that omeprazole is “susceptible to degradation in acid” (Davies Exh. 6 at 6, Exh. 7 at col. 4, 

ll. 25–30). (Davies Supp. ¶¶ 43–49, 62). Hanmi identified this same evidence in support of its 

proposed construction. (D.I. 92.1, Exh. D at 1–3).4

 

 

3

 While some salts may need to be prepared to determine whether they meet the various 

limitations of the claims (e.g., “substantially crystalline form”), that has no bearing on the 

remaining claim construction disputes or the validity of the claims. See, e.g., Enzo 

Biochem, Inc. v. Applera Corp., 599 F.3d 1325, 1336 (Fed. Cir. 2010) (“The claims are not 

indefinite even if some experimentation is required to determine the exact [scope].”); Exxon 

Res. Eng’g Co. v. U.S., 265 F.3d 1371, 1379 (Fed. Cir. 2001) (“Provided that the claims 

are enabled, and no undue experimentation is required, the fact that some experimentation 

may be necessary to determine the scope of the claims does not render the claims 

indefinite.”). 

4

 

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Now, however, Hanmi asserts that a person of ordinary skill would have 

considered esomeprazole to be compatible with acidic conditions. As explained by Dr. Davies, 

Hanmi’s evidence fails to support this position. 

Hanmi newly cites two prior art patents, U.S. Patent Nos. 4,337,257 and 

5,066,652 (the “ ’257 patent” and “ ’652 patent,” respectively) in support of this proposition. 

The ’257 patent, however, simply defines a genus of many millions of compounds and states that 

“neutral”/“free base” forms may be prepared, or “acid addition” or “basic” salts, “depending on 

the process conditions.” (Rathinam Exh. 9 at col. 2–3, 5). Nowhere does it provide a specific 

identification or exemplification of omeprazole (or one of its enantiomers) or any specific salt 

thereof, or any discussion of the behavior of omeprazole in the presence of acid. The ’652 patent 

also defines a genus that embraces many millions of compounds and similarly says nothing about 

the compatibility of omeprazole with acid. (Rathinam Exh. 10 at col. 1–2). These patents 

therefore would not inform the perspective of a person of ordinary skill as to the acid stability or 

instability of omeprazole or its enantiomers. (Davies Supp. ¶¶ 50–52). 

Hanmi also cites to a prior art abandoned German patent application, DE 

4,035,455 (“DE ’455”), which Hanmi asserts exemplifies the preparation of the (+)-enantiomer 

of omeprazole in high optical purity under acidic conditions. However, as Dr. Davies explains, it 

is not possible to assess the chemical and optical purity of the (+)-omeprazole reported in this 

reference based on the disclosure alone. Moreover, the optical and chemical purity of the (+)-

omeprazole actually reported in DE ’455 has been the subject of various proceedings involving 

the patents-in-suit or foreign equivalents thereof around the world. Evidence that has been 

presented on the DE ’455 example includes testimony of the DE ’455 inventors regarding the 

 

 

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actual experiment that is reported in DE ’455; testimony of AstraZeneca scientists who 

attempted to reproduce the DE ’455 example back in 1993 for purposes of generating material 

for toxicity studies. Dr. Davies has previously considered this evidence, and has explained that it 

supports the conclusion that the DE ’455 process provided (and provides) low yield of (+)-

omeprazole in low chemical and optical purity.5

 (Davies Supp. ¶¶ 55–61). 

In light of the foregoing, Hanmi’s conclusion that prior art patents “clearly 

establish the existence of acid addition salts” of omeprazole (Atwood Supp. ¶¶ 53–56) and that 

the “literature is replete with examples of acid salts of omeprazole” (Hanmi R. Br. 17) is without 

support.6

 

CONCLUSION 

For the foregoing reasons, AstraZeneca respectfully requests that the Court adopt 

AstraZeneca’s proposed constructions of the claim terms in dispute, as set forth in AstraZeneca’s 

prior Markman submissions in this action. 

 

5

 Hanmi has been aware of the DE ’455 evidence and of Dr. Davies’ views thereon since at 

least the July 25, 2011 service of AstraZeneca’s initial responses to Hanmi’s invalidity 

contentions. (D.I. 113.2). Nevertheless Hanmi elected not to address any of it when 

asserting that “the (+)-enantiomer was obtained” in high optical purity by the DE ’455 

method. (Atwood Supp. ¶¶ 50, 51). 

6

 Hanmi also cites to two non-prior art references, U.S. Patent No. 6,255,502 (earliest 

priority date, 1996, issued, 2001) and a 2010 article by Karthikeyan. These, of course, 

cannot inform the claim construction inquiry, Phillips, 415 F.3d at 1312–13 (claims are 

construed as of the effective filing date of the patent application), but they also would not 

change the understanding of one skilled in the art. The ’502 patent lists over a hundred 

“basic compounds” as possible options from which to prepare the acid addition salts of 

the invention, and omeprazole is included on that list. However, again, no specific salt of 

omeprazole is anywhere described or exemplified, and no discussion is given to the 

stability of omeprazole in the presence of acid. The Karthikeyan article references the 

hydrochloride salt of omeprazole, but makes no mention of its stability or chemical 

purity—without which it would not be understood to contradict the prior art teachings 

discussed above. (Davies Supp. ¶¶ 53–54). 

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 Respectfully submitted, 

Dated: March 19, 2012 By: s/ John E. Flaherty 

John E. Flaherty 

Jonathan M.H. Short 

McCARTER & ENGLISH, LLP 

Four Gateway Center 

100 Mulberry Street 

Newark, New Jersey 07102 

(973) 622-4444 

Attorneys for Plaintiffs 

ASTRAZENECA AB, 

AKTIEBOLAGET HÄSSLE, 

ASTRAZENECA LP, KBI INC. 

and KBI-E INC. 

Of Counsel: 

Henry J. Renk 

Bruce C. Haas 

Colleen Tracy 

Joshua I. Rothman 

FITZPATRICK, CELLA, HARPER 

& SCINTO 

1290 Avenue of the Americas 

New York, New York 10104-3800 

(212) 218-2100 

Einar Stole 

COVINGTON & BURLING LLP 

1201 Pennsylvania Avenue, NW 

Washington, DC 20004-2401 

(202) 662-6000 

Case 3:11-cv-00760-JAP-TJB Document 212 Filed 04/10/12 Page 9 of 10 PageID: 8636
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CERTIFICATE OF SERVICE 

I hereby certify that on March 19, 2012, I caused a copy of the foregoing ASTRAZENECA’S 

REPLY MARKMAN BRIEF and supporting documents to be served upon the following counsel 

by operation of the Court’s electronic filing system and/or electronic mail: 

Allyn Z. Lite (alite@litedepalma.com) 

Michael E. Patunas (mpatunas@litedepalma.com) 

Mayra V. Tarantino (mtarantino@litedepalma.com) 

LITE DEPALMA GREENBERG 

Two Gateway Center, 12th Floor 

Newark, New Jersey 07102 

T: (973) 623-3000 

Mark Boland (mboland@sughrue.com) 

Michael R. Dzwonczyk (mdzwonczyk@sughrue.com) 

Renita Rathinam (rrathinam@sughrue.com) 

SUGHRUE MION, PLLC 

2100 Pennsylvania Avenue, NW Suite 800 

Washington, D.C. 20037-3213 

T: (202) 293-7060 

John B. Scherling (jscherling@sughrue.com) 

SUGHRUE MION, PLLC 

4250 Executive Square, Suite 900 

La Jolla, California 92037 

T: (858) 795-1180 

 By: s/ John E. Flaherty 

 

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