Free Opening Brief in Support - District Court of Delaware - Delaware

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EXHIBIT 12

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

)
PHARMACIA & UPJOHN COMPANY, LLC )

Plaintiff,
v. SICOR INC., and SICOR PHARMACEUTICALS, INC. Defendants.

) ) )
) Civil Action No. 04-833 KAJ

)
) )

)
) )

DEFENDANTS' ANSWERS TO PLAINTIFF'S SECOND SET OF REQUESTS FOR ADMISSION (INVALIDITY) Defendants Sicor Inc. and Sicor Pharmaceuticals,Inc. ("Sicor") hereby answer the following requests for admission propounded by Plaintiff Pharmacia & Upjohn Company, LLC ("Pharmacia") pursuant to Rule 36 of the Federal Rules of Civil Procedure. GENERAL I. OBJECTIONS

Sicor bjects o totheSecond ofRequests Admission Set for (Invalidity) asbeing

overly andunduly burdensome.mong other hings, Second A t this SetofRequests Admission for isredundant toPharmacia's invalidity interrogatories and, moreover, seeks it admissions apparently related topatent claims fU.S. o Patento. 6,107,285 longereing N no b asserted by Pharmacianthisitigation, i l including claims-8and l0. 2 2. Sicor objects to the Second Set of Requests for Admission (Invalidity) to the

extent they call for Sicor to respond to admissions based upon claim terms found in claim 9 and 11-13 of the '285 patent. Determining the legal meaning of those claim terms is solely within the purview of the Court pursuant to Markman v. Westview Instruments, 517 U.S. 370 (1996). An admission under one claim construction might be inaccurate under a different construction.

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See, Tulip Computers lnt'lB. V. v. Dell Computer Corp., 210 F.R.D. 100, 108 (D. Del. 2002). As such, Sicor notes that these requests are premature and improper under Rule 36(a) because, in effect, to the exten_ they call for legal conclusions on claim interpretation. See, ld. (denying defendant's motion to compel request for admission from patent plaintiff because "requests directed towards applying the claims of the patent or requiring application of the claims prior to any Markman ruling are not the application of law to facts relevant to the case, but in reality are requests for legal conclusions and therefore, improper."). 3. To the extent the Second Set of Requests for Admission (Invalidity) allegedly do

not seek admissions based upon the legai-determined meaning of the claim terms of the '285 patent (i.e. Pharmacia's instruction that "other terms shall be given the same meaning that Sieor believes they should be given in the context of the claims of the '285 patent"), Sieor objects to Pharmacia's Second Set of Requests to Admit as attempting to elicit admissions that have a prejudicial value that far outweighs any probative value. Consequently, while Sieor responds to each Request as instructed, it will seek appropriate orders from the Court precluding introduction of these Responses at trial. REQUEST FOR ADMISSION NO. 427 The 1972 Areamone et al. reference does not disclose a physiologically acceptable solution. RESPONSE TO REQUEST FOR ADMISSION NO. 427 Denied. REQUEST FOR ADMISSION NO. 428 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside. RESPONSE TO REQUEST FOR ADMISSION Denied. NO. 428

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REQUEST FOR ADMISSION NO. 429 The 1972 Arcamone et al. reference does not disclose idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 429 Admitted. REQUEST FOR ADMISSION NO. 430 The 1972 Arcamone et al. reference does not discuss idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 430 Admitted. REQUEST FOR ADMISSION NO. 431 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of idarubicin hydrochloride. RESPONSE TO REQUEST FOR ADMISSION NO. 431 Admitted. REQUEST FOR ADMISSION NO. 432 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid. RESPONSE TO REQUEST FOR ADMISSION NO. 432 Denied. REQUEST FOR ADMISSION NO. 433 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 433 Denied. REQUEST FOR ADMISSION NO. 434 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with hydrochloric acid.

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RESPONSE TO REQUEST FOR ADMISSION NO. 434 Admitted. REQUEST FOR ADMISSION NO. 435 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 435 Admitted. REQUEST FOR ADMISSION NO. 436 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracyeline glycoside, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 436 Denied. REQUEST FOR ADMISSION NO. 437 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthraeycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydroehloride, and epirubiein hydroehloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 437 Denied. REQUEST FOR ADMISSION NO. 438 The 1972 Axcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 438 Denied.

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REQUEST FOR ADMISSION NO. 439 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracyeline glycoside selected from the group consisting of idarubicin hydroehloride, doxorubicin hydrochlofide, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 439 Denied. REQUEST FOR ADMISSION NO. 440 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthracycline glycoside is about 1 mg/ml. RESPONSE TO REQUEST FOR ADMISSION NO. 440 Admitted. The 1972 Arcamone et al. reference discloses only 0.05 mg/ml and 2 mg/mi concentrations of anthracyeline glycosides. REQUEST FOR ADMISSION NO. 441 The I972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubiein hydrochloride, doxorubicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 441 Admitted. The 1972 Arcamone et al. reference discloses only 0.05 mg/ml and 2 mg/ml concentrations of anthraeyeline glycosides. REQUEST FOR ADMISSION NO. 442 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubiein hydrochloride, doxorubicin hydroehloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with

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physiologically acceptable hydrochloric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 442 Admitted. The 1972 Arcamone et al. reference discloses only 0.05 mg/ml and 2 mg/ml concentrations of anthracycline glycosides. REQUEST FOR ADMISSION NO. 443 The 1972 Arcamone et al. reference does not disclose a physiologically acceptable solution of idarubiein hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydroehloride acid, the concentration of said anthraeyeline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 443 Admitted. REQUEST FOR ADMISSION NO. 444 The 1979 Hoffman et al. reference does not disclose a physiologically acceptable solution of idarubicin hydrochloride. RESPONSE TO REQUEST FOR ADMISSION NO. ,144 Admitted. REQUEST FOR ADMISSION NO. 445 The 1979 Hoffman et al. reference does not disclose idarubicinhydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 445 Admitted. REQUEST FOR ADMISSION NO. 446 The 1979 Hoffman et al. reference does not discuss idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 446 Admitted. REQUEST FOR ADMISSION NO. 447 The 1979 Hoffman et al. reference does not disclose a solution having a pH adjustedto from 2.5 to 5.0.

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RESPONSE TO REQUEST FOR ADMISSION NO. 447 Admitted. REQUEST FOR ADMISSION NO. 448 The 1979 Hoffman et al. reference does not disclose a solution having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 448 Admitted. REQUEST FOR ADMISSION NO. 449 The 1979 Hoffman et al. referencedoes not disclose a solution having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 449 Admitted. REQUEST FOR ADMISSION NO. 450 The 1979 Hoffinan et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 450 Admitted. REQUEST FOR ADMISSION NO. 451 The 1979 Hoffman et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubiein hydrochloride, doxorubiein hydrochloride, and epirubicin hydroehloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 451 Admitted.

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REQUEST FOR ADMISSION NO. 452 The 1979 Hoffinan et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthracycline glycoside is about 1 mg/ml. RESPONSE TO REQUEST FOR ADMISSION NO. 452 Admitted. The 1979 Hoffman et al. reference discloses only 2 mg/ml concentrations of anthracydine glycosides. REQUEST FOR ADMISSION NO. 453 The 1979 Hoffman et aI. referencedoes not disclose a physiologically acceptable solution of anthracyclineglycoside selected from the group consisting ofidarubicin hydrochloride, doxombicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 453 Admitted. REQUEST FOR ADMISSION NO. 454 The 1979 Hoffman et al. reference does not disclose a physiologically acceptable solution of authraeycline glycoside selected from the group consisting of idarubicin hydrochloride, doxombiein hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthraeycline glycoside being about 1 mg/ml, wherein said solution s contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 454 Admitted. REQUEST FOR ADMISSION NO. 455 The 1979 Hoffman et al. reference does not disclose a physiologieaUy acceptable solution of anthracycline glycoside dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 455 Admitted.

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REQUEST FOR ADMISSION NO. 456 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution. RESPONSE TO REQUEST FOR ADMISSION NO. 456 Denied. REQUEST FOR ADMISSION NO. 457 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of authracycline glycoside. RESPONSE TO REQUEST FOR ADMISSION NO. 457 Denied. REQUEST FOR ADMISSION NO. 458 The 1985 Janssen et al. reference does not disclose idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 458 Admitted. REQUEST FOR ADMISSION NO. 459 The 1985 Jaussen et al. reference does not discuss idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 459 Admitted. REQUEST FOR ADMISSION NO. 4611 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of idarubiein hydroehloride. RESPONSE TO REQUEST FOR ADMISSION NO. 460 Admitted. REQUEST FOR ADMISSION NO. 461 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid. RESPONSE TO REQUEST FOR ADMISSION NO. 461 Denied.

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REQUEST FOR ADMISSION NO, 462 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthraeycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 462 Denied. REQUEST FOR ADMISSION NO, 463 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthraeycline glycoside having a pH adjusted to from 2.5 to 5.0 with hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 463 Denied. REQUEST FOR ADMISSION NO. 464 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 464 Denied. REQUEST FOR ADMISSION NO. 465 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 465 Denied. REQUEST FOR ADMISSION NO. 466 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 466 Denied. REQUEST FOR ADMISSION NO. 467 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthraeycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically 10

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acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 467 Denied. REQUEST FOR ADMISSION NO. 468 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 468 Denied. REQUEST FOR ADMISSION NO. 469 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthraeycline glycoside selected from the group consisting ofidarubicin hydrochloride, doxombicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 469 Denied. REQUEST FOR ADMISSION NO. 470 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthraeyeline glycoside is about 1 mg/ml. RESPONSE TO REQUEST FOR ADMISSION NO. 470 Admitted. The 1985 Janssen et al. reference discloses anthracyeline glycoside concentrations of only about 0.05 mg/ml, 0.1 mg/ml, and 0.50 mg/ml. REQUEST FOR ADMISSION NO. 471 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of artthracycline glycoside selected from the group consisting of idarubicin hydrocb.loride, 11

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doxorubiein hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR AD_SSION NO. 471

Admitted. The 1985 Janssen et al. reference discloses anthracycline glycoside concentrations of only about 0.05 mg/ml, 0.1 mg/ml, and 0.50 mg/ml. REQUEST FOR ADMISSION NO. 472 The 1985 Janssen et al. reference does not disclose a physiologically acceptable solution of idarubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthraeycline glycoside being about 1 rag/m1, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 472 Admitted. The 1985 Janssen et al. reference discloses only doxorubicin hydrochioride in concentrations of only about 0.05 mg/ml, 0.1 mg/mi, and 0.50 mg/ml. REQUEST FOR ADMISSION NO. 473 The 1981 Ketchum et al. reference does not disclose a physiologically acceptable solution of idarubicin hydrochloride. RESPONSE TO REQUEST FOR ADMISSION NO. 473 Admitted. REQUEST FOR ADMISSION NO. 474 The 1981 Ketchum et al. reference does not disclose idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 474 Admitted. REQUEST FOR ADMISSION NO. 475 The 1981 Ketchum et al. reference does not disclose idarubicin hydroehloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 475 Admitted. 12

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REQUEST FOR ADMISSION NO. 476 The 1981 Ketchum et al. reference does not disclose a solution having a pH adjusted to from 2.5 to 5.0. RESPONSE TO REQUEST FOR ADMISSION NO. 476 Denied. REQUEST FOR ADMISSION NO. 477 The 1981 Ketchum et al. reference does not disclose a solution having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfortic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 477 Admitted. REQUEST FOR ADMISSION NO. 478 The 1981 Ketchum et al. reference does not disclose a solution having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 478 Admitted. REQUEST FOR ADMISSION NO. 479 The 1981 Ketehum et al. reference does not disclose a physiologically acceptable solution ofanthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 479 Admitted. REQUEST FOR ADMISSION NO. 480 The 1981 Ketchum et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubicin hydroehloride, doxorubicin hydrochloride, and epirubiein hydroehloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids.

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RESPONSE TO REQUEST FOR ADMISSION NO. 480 Admitted. REQUEST FOR ADMISSION NO. 481 The 1981 Ketchum et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthracycline glycoside is about 1 mg/ml. RESPONSE TO REQUEST FOR ADMISSION NO. 481 Admitted. 1981 Ketehum et al. reference discloses a physiologically acceptable solution of anthraeycline glycoside wherein the concentration of anthracyefine glycoside is only about 0.01 mg/ml and 2.0 mg/ml. REQUEST FOR ADMISSION NO. 482 The 1981 Ketchum et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubiein hydroehloride, doxorubiein hydrocb_loride,and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 482 Admitted. REQUEST FOR ADMISSION NO. 483 The 1981 Ketchum et al. reference does not disclose a physiologicaUy acceptable solution of anthracyeline glycoside selected from the group consisting of idarubicin hydroehloride, doxorubicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 483 Admitted. REQUEST FOR ADMISSION NO. 484 The 1981 Ketchum et al. reference does not disclose a physiologically acceptable solution of idarubicin hydroehloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the

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concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 484 Admitted. REQUEST FOR ADMISSION NO. 485 The 1976 Lachman et al. reference does not teach that buffers contribute to degradation. RESPONSE TO REQUEST Denied. REQUEST FOR ADMISSION NO. 486 The 1976 Lachman et al. reference does not teach that buffers necessarily contribute to degradation, only that they "can catalyze the degradation." RESPONSE TO REQUEST FOR ADMISSION NO. 486 Denied. REQUEST FOR ADMISSION NO. 487 The 1976 Lachman et al. reference does not teach that one should use hydrochloric acid to adjust pH. RESPONSE TO REQUEST FOR ADMISSION NO. 487 Denied. REQUEST FOR ADMISSION NO. 488 The 1976 Lachman et al. reference does not teach that one should use hydrochloric acid instead of a buffer to adjust pH. RESPONSE TO REQUEST FOR ADMISSION NO. 488 Denied. REQUEST FOR ADMISSION NO. 489 The 1976 Lachman et al. reference does not discuss hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 489 Admitted. Chapter 2 of Laehman et al. (1976) The Theory. and Practice of Industrial Pharmacy, which Pharmacia designated as "1976 Lachman et al. reference" does not discuss hydrochloric acid; however, Chapter 1 of Laehman et al. (1976) The Theory. 15 FOR ADMISSION NO. 485

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and Practice of Industrial Pharmacy, entitled "Preformulatiou," does discuss hydrochloric acid. REQUEST FOR ADMISSION NO. 490 The 1976Lachmanetal. eference notdiscuss useofhydrochloric toadjust r does the acid

pH.
RESPONSE TO REQUEST Admitted. FOR ADMISSION NO. 490

Chapter 2 of Lachman et aL (1976) The Theory. and Practice of

Industrial Pharmacy, which Pharmacia designated as "1976 Laehman et al. reference" does not discuss the use of hydrochloric acid to adjust pH; however, Chapter 1 of Lachmau et aL (1976) The Theory and Practice of Industrial Pharmacy, entitled "Preformulation," does discuss the use of hydrochloric acid to adjust pH. REQUEST FOR ADMISSION NO. 491 The 1976 Lachman et al. reference teaches that, "[i]f the degradation reaction is found to be influenced by different concentration of buffer [sic], then .... the concentration of the buffer ratio should be kept as low as possible to diminish the catalytic effect. [sic]" RESPONSE TO REQUEST FOR ADMISSION NO. 491 Sicor admits that the 1976 Lachman et aL reference states that, "[i]f the degradation reaction is found to be influenced by the different concentrations of buffer, then the reaction is considered to be general acid and base catalyzed. In such a case, the concentration of the buffer ratio should be kept as low as possible to diminish this catalytic effect." One of ordinary skill in the art would infer that "the concentration of the buffer ratio should be kept as low as possible" to include omission of buffer from a pharmaceutical solution. REQUEST FOR ADMISSION NO. 492 The 1976 Lachmau et al. reference does not suggest the use of hydrochloric acid to adjust pH, instead teaching that buffer concentration should be kept as low as possible to diminish the catalytic effect. RESPONSE TO REQUEST FOR ADMISSION NO. 492

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Denied. REQUEST FOR ADMISSION NO. 493 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution. RESPONSE TO REQUEST FOR ADMISSION NO. 493 Denied. REQUEST FOR ADMISSION NO. 494 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthraeyeline glycoside. RESPONSE TO REQUEST FOR ADMISSION NO. 494 Denied, REQUEST FOR ADMISSION NO. 495 The April 1980 Mori et al. reference does not disclose idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 495 Admitted. REQUEST FOR ADMISSION NO. 496 The April 1980 Mori et al. reference does not discuss idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 496 Admitted. REQUEST FOR ADMISSION NO. 497 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of idarubicin hydrochloride. RESPONSE TO REQUEST FOR ADMISSION NO. 497 Admitted. REQUEST FOR ADMISSION NO. 498 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthraeyeline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid. RESPONSE TO REQUEST FOR ADMISSION NO. 498 17

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Denied. REQUEST FOR ADMISSION NO. 499 The April 1980 Mori et al. referencedoes not disclose a physiologically acceptable solution of anthracyclineglycoside having a pH adjustedto from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 499 Denied. REQUEST FOR ADMISSION NO. 500 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 500 Denied. REQUEST FOR ADMISSION NO. 501 The April 1980 Mori et aL reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 501 Denied. REQUEST FOR ADMISSION NO. 502 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 502 Denied. REQUEST FOR ADMISSION NO. 503 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracyeline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container.

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RESPONSE TO REQUEST FOR ADMISSION NO. 503 Admitted. REQUEST FOR ADMISSION NO. 504 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 504 Denied. REQUEST FOR ADMISSION NO. 505 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracyeline glycoside selected from the group consisting of idarubicin hydroehloride, doxorubicin hydrochloride, and epirubiein hydrochloride dissolved in a physiologically aeceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 505 Admitted. REQUEST FOR ADMISSION NO. 506 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the coneentratiort of anthracycline glycoside is about

1 rng/ml.
RESPONSE TO REQUEST FOR ADMISSION NO. 506 Admitted. The April 1980 Mori et al. reference discloses only 2 mg/ml concentrations of anthracycline glycosides. REQUEST FOR ADMISSION NO. 507 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracyeline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride, and epirubicin hydroehloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said 19

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anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 507 Admitted. REQUEST FOR ADMISSION NO. 508 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydroehloride, and epirubicin hydroehloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable hydrochloric acid, the concentration of said anthracyeline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 508 Admitted. REQUEST FOR ADMISSION NO. 509 The April 1980 Mori et al. reference does not disclose a physiologically acceptable solution of idarubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthraeycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 509 Admitted. REQUEST FOR ADMISSION NO. 510 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution. RESPONSE TO REQUEST FOR ADMISSION NO. 510 Denied. REQUEST FOR ADMISSION NO. 511 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthraeycline glycoside. RESPONSE TO REQUEST FOR ADMISSION NO. 511 Denied.

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REQUEST FOR ADMISSION NO. 512 The May 1980 Mori et al. reference does not disclose idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 512 Admitted. REQUEST FOR ADMISSION NO. 513 The May 1980 Mori et al. reference does not discuss idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 513 Admitted. REQUEST FOR ADMISSION NO. 514 The May 1980 Moil et al. reference does not disclose a physiologically acceptable solution of idarubicin hydroehloride. RESPONSE TO REQUEST FOR ADMISSION NO. 514 Admitted. REQUEST FOR ADMISSION NO. 515 The May 1980 Moil et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid. RESPONSE TO REQUEST FOR ADMISSION NO. 515 Denied. REQUEST FOR ADMISSION NO. 516 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 516 Admitted. REQUEST FOR ADMISSION NO. 517 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with hydrochloric acid.

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RESPONSE TO REQUEST FOR ADMISSION NO. 517 Admitted. REQUEST FOR ADMISSION NO. 518 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution ofanthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 518 Admitted. REQUEST FOR ADMISSION NO. 519 The May 1980 Mori et aI. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 519 Denied. REQUEST FOR ADMISSION NO. 520 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting ofidarubicin hydrochloride, doxorubiein hydroehloride, and epirubiein hydroehloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said antlaraeyeline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 520 Admitted. REQUEST FOR ADMISSION NO. 521 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQL_ESTFOR ADMISSION NO. 521 Admitted.

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REQUEST FOR ADMISSION NO. 522 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubiein hydrochloride, doxombicin hydrocb_loride,and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonie acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 522 Admitted. REQUEST FOR ADMISSION NO. 523 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthracycline glycoside is about 1 mg/ml. RESPONSE TO REQUEST FOR ADMISSION NO. 523 Admitted. The May 1980 Mori et a£ reference discloses only 2 mg/ml concentrations of anthracycUne glycosides. REQUEST FOR ADMISSION NO. 524 The May 1980 Mort et al. reference does not disclose a physiologically acceptable solution of anthracyeline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride, and epirubiein hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 524 Admitted. REQUEST FOR ADMISSION NO. 525 The May 1980 Mori et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride, and epirubiein hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthracyeline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container.

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RESPONSE

TO REQUEST

FOR ADMISSION

NO. 525

Admitted. REQUEST FOR ADMISSION NO. 526 The May 1980 Mori et al. reference does not disciose a physiologically acceptable solution of idambicin hydtochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 526

Admitted. REQUEST FOR ADMISSION NO. 527 The May 1980 Mori et al. reference does not suggest that pharmaceutical preparations of anthracycline glycosides should be in solution, instead stating, "In pharmaceutical preparations of ACM-HCI, therefore, it should be lyophilized or dry-filled into ampules or vials with a stabilizer including lactose or maltose." RESPONSE TO REQUEST FOR ADMISSION NO. 527

Sicor denies that the May 1980 Mori et ai. reference does not suggest that pharmaceutical preparations of anthracyeline glycosides should be in solution. Sicor

admits that the May 1980 Mori et al. reference states, "The effects of various diluents on stability of ACM-HCI, freeze-dried ACM-HCI preparations and closed under vacuum in vials, was examined. In pharmaceutical

was moderately stabilized by addition of lactose or maltose. of ACM-HCI, therefore, it should be iyophilized

or dry-f'dled into ampules or

vials with a stabilizer including lactose or maltose." REQUEST FOR ADMISSION NO. 528 The 1981 Poochikian et al. reference does not disclose a physiologically solution of idarubicin hydrochloride. RESPONSE TO REQUEST FOR ADMISSION NO. 528

acceptable

Admitted. REQUEST FOR ADMISSION NO. 529 The 1981 Poochikian et al. reference does not disclose idarubicin hydrochloride in any formulation. 24

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RESPONSE TO REQUEST FOR ADMISSION NO. 529 Admitted. REQUEST FOR ADMISSION NO. 530 The 1981 Poochikian et al. reference does not discuss idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 530 Admitted. REQUEST FOR ADMISSION NO. 531 The 1981 Poochikian et al. reference does not disclose a solution having a pH adjusted to from 2.5 to 5.0. RESPONSE TO REQUEST FOR ADMISSION NO. 531 Denied. REQUEST FOR ADMISSION NO. 532 The 1981 Poochikian et al. reference does not disclose a solution havinga pHadjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 532 Denied. REQUEST FOR ADMISSION NO. 533 The 1981 Poochikian et al. reference does not disclose a solution having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 533 Den_d. REQUEST FOR ADMISSION NO. 534 The 1981 Poochikian et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 534 Admitted. 25

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REQUEST FOR ADMISSION NO. 535 The 1981 Poochikian et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubiein hydrochlofide, and epirubiein hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracyeline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 535 Admitted. REQUEST FOR ADMISSION NO. 536 The 1981 Poochikian et aL reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthracycline glycoside is about 1 mg/ml. RESPONSE TO REQUEST FOR ADMISSION NO. 536 Admitted. The 1981 Poochikian et al. reference discloses only 0.01 mg/ml, 0.02 mg/ml, and 2 mg/ml concentrations of anthracycline glycosides. REQUEST FOR ADMISSION NO. 537 The 1981 Poochikian et al. reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting ofidarubiein hydroehloride, doxorubicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 537 Admitted. REQUEST FOR ADMISSION NO. 538 The 1981 Poochikian et al. reference does not disclose a physiologically acceptable solution ofanthracyeline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable hydrochloric acid, the concentration of said anthracyeline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container.

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RESPONSE TO REQUEST FOR ADMISSION NO. 538 Admitted. REQUEST FOR ADMISSION NO. 539 The 1981 Poochikian et al. reference does not disclose a physiologically acceptable solution of idarubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pit adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 539 Admitted. REQUEST FOR ADMISSION NO. 540 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution. RESPONSE TO REQUEST FOR ADMISSION NO. 540 Denied. REQUEST FOR ADMISSION NO. 541 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside. RESPONSE TO REQUEST FOR ADMISSION NO. 541 Den_d. REQUEST FOR ADMISSION NO. 542 The 1980 Vigevani & Williamson reference does not disclose idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 542 Admitted. REQUEST FOR ADMISSION NO. 543 The 1980 Vigevaxti & Williamson reference does not discuss idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 543 Admitted.

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REQUEST FOR ADMISSION NO. 544 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of idarubicin hydrochlodde. RESPONSE TO REQUEST FOR ADMISSION NO. 544 Admitted. REQUEST FOR ADMISSION NO. 545 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthraeycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid. RESPONSE TO REQUEST FOR ADMISSION NO. 545 Admitted. REQUEST FOR ADMISSION NO. 546 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 546 Admitted. REQUEST FOR ADMISSION NO. 547 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with hydrocb_loric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 547 Admitted. REQUEST FOR ADMISSION NO. 548 The 1980 Vigevani & WiUiamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 548 Admitted.

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REQUEST FOR ADMISSION NO. 549 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 549 Admitted. REQUEST FOR ADMISSION NO. 550 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubicin hydrochlofide, doxorubicin hydrochloride, and epirubiein hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 550 Admitted. REQUEST FOR ADMISSION NO. 551 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 551 Admitted. REQUEST FOR ADMISSION NO. 552 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubicin hydroehloride, doxorubicin hydrochloride, and epirubiein hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 552 Admitted. 29

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REQUEST FOR ADMISSION NO. 553 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthracycline glycoside is about 1 mg/ml. RESPONSE TO REQUEST FOR ADMISSION NO. 553 Admitted. REQUEST FOR ADMISSION NO. 554 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting ofidambicin hydrochloride, doxombicin hydrochloride, and epirubiein hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, the concentration of said anthracycline glycoside being about 1 rag/m1, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 554 Admitted. REQUEST FOR ADMISSION NO. 555 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting ofidarubicin hydrochloride, doxombicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologieaUy acceptable hydrochloric acid, the concentration of said anthracycline glycoside being about 1 rag/m1, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 555 Admitted. REQUEST FOR ADMISSION NO. 556 The 1980 Vigevani & Williamson reference does not disclose a physiologically acceptable solution of idarubicin hydrochlodde dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid, the concentration of said anthracyeline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 556 Admitted.

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REQUEST FOR ADMISSION NO. 557 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution. RESPONSE TO REQUEST FOR ADMISSION NO. 557 Denied. REQUEST FOR ADMISSION NO. 558 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthraeycline glycoside. RESPONSE TO REQUEST FOR ADMISSION NO. 558 Denied. REQUEST FOR ADMISSION NO. 559 The 1983 Wassermann & Bundgaard reference does not disclose idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 559 Admitted. REQUEST FOR ADMISSION NO. 560 The 1983 Wassermann & Bundgaard reference does not discuss idarubicin hydrochloride in any formulation. RESPONSE TO REQUEST FOR ADMISSION NO. 560 Admitted. REQUEST FOR ADMISSION NO. 561 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of idarubicin hydrochloride. RESPONSE TO REQUEST FOR ADMISSION NO. 561 Admitted. REQUEST FOR ADMISSION NO. 562 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid. RESPONSE TO REQUEST FOR ADMISSION NO. 562

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Admitted. The 1983 Wassermann & Bundgaard reference does disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 0.43 to 2.13 with a physiologically acceptable acid, which one of ordinary skill in the art would recognize falls within the range of pH of the human stomach. REQUEST FOR ADMISSION NO. 563 The 1983 Wassermann & Bundgaxtrd reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 563 Admitted. The 1983 Wassermann & Bundgaard reference does disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 0.43 to 2.13 with a physiologically acceptable acid in the form of hydrochloric acid, which one of ordinary skill in the art would recognize falls within the range of pH of the human stomach. REQUEST FOR ADMISSION NO. 564 The 19_3 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 564 Admitted. The 1983 Wassermann & Bundgaard reference does disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 0.43 to 2.13 with hydrochloric acid, which one of ordinary skill in the art would recognize falls within the range of pH of the human stomach. REQUEST FOR ADMISSION NO. 565 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 2.5 to 5.0 with physiologically acceptable hydrochloric acid. RESPONSE TO REQUEST FOR ADMISSION NO. 565

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Admitted. The 1983 Wassermann & Bundgaard reference does disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 0.43 to 2.13 with physiologically acceptable hydrochloric acid, which one of ordinary skill in the art would recognize falls within the range of pH of the human stomach. REQUEST FOR ADMISSION NO. 566 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthracycline glycoside, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 566 Denied. REQUEST FOR ADMISSION NO. 567 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting ofidarubicin hydrochloride, doxorubicin hydrochlodde, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, the tartaric acid, the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO. 567 Admitted. REQUEST FOR ADMISSION NO. 568 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthracycline glycoside, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 568 Admitted. The 1983 Wassermann & Bundgaard reference does disclose a physiologically acceptable solution of anthracycline glycoside having a pH adjusted to from 0.43 to 2.13 with a physiologically acceptable acid in the form of hydrochloric acid. One of ordinary skill in the art would recognize that the 1983 Wassermann & Bundgaard

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reference teaches that said solution would exhibit storage stability at 4 °C as a result of said pH being adjusted to a higher pH using hydrochloric acid. REQUEST FOR ADMISSION NO. 569 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthraeyeline glycoside selected from the group consisting of idarubicin hydroehloride, doxorubicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, the tartaric acid, the concentration of said anthracyeline glycoside being from 0.1 to 100 mg/ml, wherein said solution is contained in a sealed container, wherein said solution exhibits storage stability as a result of said pH being adjusted to the said range using said acids. RESPONSE TO REQUEST FOR ADMISSION NO. 569 Adm_ted. REQUEST FOR ADMISSION NO. 570 The 1983 Wassermann & Bundgaard reference does not disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthracycline glycoside is about 1 mg/ml. RESPONSE TO REQUEST FOR ADMISSION NO. 570 Admitted. The 1983 Wassermann & Bundgaard reference does disclose a physiologically acceptable solution of anthracycline glycoside wherein the concentration of anthracycline glycoside is about 0.0012 mg/ml. REQUEST FOR ADMISSION NO. 571 The 1983 Wassermann & Btmdgaard reference does not disclose a physiologically acceptable solution of anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride, and epirubicin hydrochloride dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologicaUy acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, the tartaric acid, the concentration of said anthracycline glycoside being about 1 mg/ml, wherein said solution is contained in a sealed container. RESPONSE TO REQUEST FOR ADMISSION NO.