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

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EXHIBIT 13

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE

PHARMACIA & UPJOHN COMPANY, Plaintiff,
V,

Civil Action No. 04-833

SICOR, INC. and SICOR PHARMACEUTICALS INC., Defendants.

DEFENDANTS' RESPONSES TO PHARMACIA & UPJOHN'S THIRD SET OF INTERROGATORIES Defendants Sicor Inc. and SICOR Pharmaceuticals, Inc. (collectively "Defendants" or "Sicor"), by and through its undersigned counsel, for their responses to the Third Set of Interrogatories by Plaintiff Pharmacia & Upjohn Company LLC ("Plaintiff' or "Pharmacia'), state as follows:

GENERAL OBJECTIONS Defendants incorporate their general and specific objections from their responses to Plaintiffs' prior sets of Interrogatories,in addition: 1. Defendants object to the Third Set of Interrogatories because they call for

Defendants to respond based upon the meaning of 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 pursuantto Markman v, Westview Instruments, 517 U.S. 370 (1996). To the extent these Interrogatories allegedly do not seek responses based upon the legal-determined meaning of the claim teas of the '285 patent (i.e. Pharmacia's instruction that "other terms shall be given

the same meaning that Sicor believes they should be given in the context of the claims of the

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'285 patent"), Sicor objects to Pharmacia's Third Set of Interrogatories as attempting to elicit responses that have a prejudicial value that far outweighs any probative value. Consequently, while Defendants respond to each Interrogatory as instructed, they will seek appropriate orders from the Court precluding introduction &these responses at trial. 2. Defendants object to the Third Set of Interrogatories because they call for an

inappropriate parsing of certain prior art references. Defendants have asserted claims of invalidity based on both anticipation and obviousness. Obviousness looks to the scope of the prior art as a whole and its teachings to one of ordinary skill in the art as compared to the claimed invention. As such, these Interrogatories fall short of addressing this basic inquiry. Subject to the foregoing general objections, Defendants respond as follows: SPECIFIC RESPONSES INTERROGATORYNO. 11 With regard to the 1985 Janssen et al. reference, (i) identify with specificity each and every limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation. RESPONSE TO INTERROGATORY NO. 11 Limitations from Asserted Claim 9 A physiologically acceptable solution of 1985 Janssen et al. reference "--A--i-'pH----4--._n.0 nos-_g'_composition was| observed; this holds for DXR solutions and I liposome dispersions (in Tris as well as inphosphate buffer) that were stored for at least 40 days protected from light at 4°C. At pH 4.0 the buffer capacity of the Tris buffer is low. However, this system provides physicochemically well-defined and stable DXR-eontaining liposomes (Crommelin et al., 1983; Crommelin and Van Bloois, 1983). These dispersions were successfully tested in vivo (Van Hoesel et al., 1984)." (Conclusions, p.9).

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anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochlorideand epirubicin hydrochloride

"Doxorubicin-HC1 and doxorubicinone-HC1 were provided by Farmitalia (Milan) and Lab. Roger Bellon (Neuilly sur Seine, Paris)" (Materials and Methods Reagents, p.2)

dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

"An HPLC technique was used to monitor the stability of doxombicin-HC1 (DXR) in aqueous media." (Summary, p.1)(emphasis added).

"Tris buffers with pH 7.4 or 4.0:0.01 mol/l Tris and 0.8% sodium chloride. The pH was adjusted with 2 mol/l hydrochloric acid." (Incubation media, p.4)(emphasis added) with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, "The pH was adjusted with 2 mol/l hydrochloric acid." (Incubation media, p.4)

"At pH 4.0 no significant decomposition was observed; this holds for DXR solutions and liposome dispersions (in Tris as well as in phosphate buffer) that were stored for at least 40 days protected from light at 4°C. At pH 4.0 the buffer capacity of the Tris buffer is low." (Conclusions, p.9).

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the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml,

"One ml samples of DXR-containing solutions ... (100 p.g/ml) were incubated in various buffers in 10 ml glass vials in a refrigerator." (Incubations at 4°C, p.4).

wherein said solution is contained in a sealed container

"One ml samples of DXR-containing solutions . .. (100 _g/ml) were incubated in various buffers in 10 ml glass vials in a refrigerator." (Inc_ations at 4°C, p.4). "In some cases polypropylene tubes were used, too, for comparison." (Incubations at 4°C, p.4). It necessarily follows from good laboratory practice and simple common sense, and thus would be understood by one skilled in the art, that the containers (i.e., vials and tubes) disclosed in Janssen were sealed to avoid contamination, evaporation, and dangerous exposure of the researchers to doxorubicin, which is a highly cytotoxic agent that requires extreme care in handling.

wherein said solution exhibits storage stability as a result of said pH being adjusted to the said pH range using said acids,

"The results obtained in this study indicated that pH 4 and 4°C provide optimum shelf-life conditions." (Summary, p. 1) "The DXR concentration was determined as a function of time in aqueous solutions and liposome dispersions. In both buffer systems no significant DXR degradation was recorded over a 60-day period of storage at pH 4.0." (Results and Discussion, p.5) "At pH 4.0 no significant decomposition was observed; this holds for DXR solutions and liposome dispersions (in Tris as well as in phosphate buffer) that were stored for at least 40 days protected from light at 4°C. At pH 4.0 the buffer capacity of the Tris buffer is low." (Conclusions, p.9).

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Limitations from Asserted Claim 11 A physiologically acceptable solution of

1985 Janssen et al. reference "At pH 4.0 no significant decomposition was observed; this holds for DXR solutions and iiposome dispersions (in Tris as well as in phosphate buffer) that were stored for at least 40 days protected from light at 4°C. At pH 4.0 the buffer capacity of the Tris buffer is low. However, this system provides physicochcmically well-defined and stable DXR-containing liposomes (Crommelin et al., 1983; Crommelin and Van Bloois, 1983). These dispersions were successfully tested in vivo (Van Hoesel et al., 1984)." (Conclusions, p.9).

anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicinhydrochlorideandepirubicin hydrochloride

"Doxorubicin-HC1 and doxorubicinone-HC1 were provided by Farmitalia (Milan) and Lab. Roger Bellon (Neuilly sur Seine, Paris)" (Materials and Methods Reagents, p.2)

dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

"An HPLC technique was used to monitor the stability of doxorubicin-HC1 (DXR) in aqueous media," (Summary, p.1)(emphasis added).

"Tris buffers with pH 7.4 or 4.0:0.01 mol/1 Tris and 0.8% sodium chloride. The pH was adjusted with 2 molfl hydrochloric acid." (Incubation media, p.4)(emphasis added)

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with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid,

"The pH was adjusted with 2 mol/l hydrochloric acid." (Incubation media, p.4)

"At pH 4.0 no significant decomposition was observed; this holds for DXR solutions and liposome dispersions (in Tris as well as in phosphate buffer) that were stored for at least 40 days protected from light at 4°C. At pH 4.0 the buffer capacity of the Tris buffer is low." (Conclusions, p.9). wherein said solution is contained in a sealed container "One ml samples of DXR-containing solutions . .. (100 gg/ml) were incubated in various buffers in 10 ml glass vials in a refrigerator." (Incubations at 4°C, p.4). "In some cases polypropylene tubes were used, too, for comparison." (Incubations at 4°C, p.4). It necessarily follows from good laboratory practice and simple common sense, and thus would be understood by one skilled in the art, that the containers (i.e., vials and tubes) disclosed in Janssen were sealed to avoid contamination, evaporation, and dangerous exposure of the researchers to doxorubicin, which is a highly cytotoxic agent that requires extreme care in handlixtg.

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Limitations from Asserted Claim 12 A physiologically acceptable solution of

1985 Janssen et al. reference "At pH 4.0 no significant decomposition was observed; this holds for DXR solutions and liposome dispersions (in Tris as well as in phosphate buffer) that were stored for at least 40 days protected from light at 4°C. At pH 4.0 the buffer capacity of the "Iris buffer is low. However, this system provides physicochemicany well-defined and stable DXR-containing liposomes (Crommelin et al., 1983; Crommelin and Van Bloois, 1983). These dispersions were successfully tested in vivo (Van Hoesel et al., 1984)." (Conclusions, p.9).

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

"Doxorubicin-HC1 and doxorubicinone-HC1 were provided by Farmitalia (Milan) and Lab. Roger Bellon (Neuilly sur Seine, Paris)" (Materials and Methods Reagents, p.2) "An HPLC technique was used to monitor the stability of doxorubicin-HC1 (DXR) in aqueous media." (Summary, p.1)(emphasis added).

"Tris buffers with pH 7.4 or 4.0:0.01 mol/1 Tris and 0.8% sodium chloride. The pH was adjusted with 2 mol/l hydrochloric acid." (Incubation media, p.4)(emphasis added)

with a physiologically acceptable acid, wherein the physiologically acceptable acid is hydrochloric acid, wherein said solution is contained in a sealed container

"The pH was adjusted with 2 mol/1 hydrochloric acid." (Incubation media, p.4)

"One ml samples of DXR-containing solutions ... (100 _tg/ml)were incubated in various buffers in l 0 ml glass vials in a refrigerator." (Incubations at 4°C, p.4). "In some cases polypropylene tubes were used, too, for comparison." (Incubations at 4°C, p.4). It necessarily follows from good laboratory _ractice and simple common sense, and thus 7

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would be understood by one skilled in the art, that the containers (i.e., vials and tubes) disclosed in Janssen were sealed to avoid contamination, evaporation, and dangerous exposure of the researchers to doxorubicin, which is a highly cytotoxic agent that requires extreme care in handling.

Limitations from Asserted Claim 13 A physiologically acceptable solution of

1985 Janssen et aL reference "At pH 4.0 no significant decomposition was observed; this holds for DXR solutions and liposome dispersions (in Tris as well as in phosphate buffer) that were stored for at least 40 days protected from light at 4°C. At pH 4.0 the buffer capacity of the Tris buffer is low. However, this system provides physicochemically well-defined and stable DXR-containing liposomes (Crommelin et al., 1983; Crommelin and Van Bloois, 1983). These dispersions were successfully tested in vivo (Van Hoesel et al., 1984)." (Conclusions, p.9). "An HPLC technique was used to monitor the stability of doxorubicin-HC1 (DXR) in aqueous media." (Summary, p. 1)(emphasis added).

dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

"Tris buffers with pH 7.4 or 4.0:0.01 mol/l Tris and 0.8% sodium chloride. The pH was adjusted with 2 mol/l hydrochloric acid." (Incubation media, p.4)(emphasis added)

with a physiologically acceptable acid, wherein the physiologically acceptable acid is hydrochloric acid,

"The pH was adjusted with 2 mol/1 hydrochloric acid." (Incubation media, p.4)

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wherein said solution is contained in a sealed container

"One ml samples of DXR-containing solutions ... (100 _tg/ml) were incubated in various buffers in 10 ml glass vials in a refrigerator." (Incubations at 4°C, p.4). "In some cases polypropylene tubes were used, too, for comparison." (Incubations at 4°C, p.4). It necessarily follows from good laboratory ...... ,,.,.,,., o,,,,v,,,common sense, mad"thus would be understood by one skilled in the art, that the containers (i.e., vials and tubes) disclosed in Janssen were sealed to avoid contamination, evaporation, and dangerous exposure of the researchers to doxombicin, which is a highly cytotoxic agent that requires extreme care in handling.

INTERROGATORY NO. 12 With regarding to the 1983 Wassermann & Bundgaard reference, (i) identify with specificity each and every limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation. RESPONSE TO INTERROGATORY NO. 12 Limitations from Asserted Claim 9 A physiologically acceptable solution of 1983 Wassermann & Bundgaard reference "Samples of doxorubicin hydrochloride and doxorubicinone were kindly provided by Farmltalia Milan. Italy. Buffer substances and all other chemicals and solvents used were of reagent grade." (Materials, p.74)

t___

stability may be useful to assess the extent of possible degradation of the drug in the stomach after oral administration." I "Furthermore, knowledge about the acidI (Introduction, p.74)

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anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride and epirubicin hydrochloride

_"Samplesof doxorubicin hydrochloride and doxorubicinone were kindly provided by Farmltalia Milan, Italy. Buffer substances and all other chemicals and solvents used were of reagem grade." (Materials, p.74) "The purpose of this study was to provide information about the kinetics of hydrolysis of doxorubicin in acidic solution." (Introduction, p.74) "In 0.01-0.5M hydrochloric acid solutions (pH 0.4-2.1)," (Results and discussion, p.75). See also, Fig. 2, p.75 showing first-order hydrolysis reaction plots in 0.1 and 0.5M hydrochloric acid. "The reaction solutions were kept in a thermostatically controlled water bath (±0.3°C) in screw-capped tubes protected from light and the reactions were initiated by dissolving a weighted quantity of doxorubicin hydrochloride in the pre-heated buffer solution to give an initial concentration of about 1.2 p.g*ml"1.'' (Kinetic Measurements, p.75)(emphasis added).

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,

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 pH range using said acids,

"[T]he percentage amount ofdoxorubicin surviving acid-catalyzed degradation in the stomach can be calculated using the following equation for two parallel first-order processes:

The figures derived in this way are 86% for pH 1 and 98% for pH 2. Thus, acid-catalyzed hydrolytic degradation in the stomach of orally administered doxorubicin appears to be of minor importance." (Results and discussion, p.77) "The rate data presented may also be useful to assess the potential detrimental effect of a pH 2 mobile phase in HPLC of doxorubicine and related anthracycline antibiotics as claimed by Haneke et al (1981). At 2°C and pH 2 (pure aqueous solution) the time needed for hydrolyzing doxorubicin to an extent of 1% 10

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the utilization of a mobile phase with a pH of 2 appears not to be unacceptable in regard to hydrolytic degradation of the drug..." (Results and discussion, p.77) can be calculated to be about 80 min. Thus,

Limitations from Asserted Claim 11 A physiologically acceptable solution of

1983 Wassermann & Bundgaard reference "Samples of doxorubicin hydrochioride and doxorubicinone were kindly provided by Farmltalia Milan. Italy. Buffer substances and all other chemicals and solvents used were of reagent grade." (Materials, p.74) "Furthermore, knowledge about the acidstability may be useful to assess the extent of possible degradation of the drug in the stomach after oral administration." (Introduction, p.74)

anthracycline glycoside selected from the group consisting of idarubiein hydrochloride, doxorubicin hydrochloride and epirubicin hydrochloride

"Samples of doxorubicin hydrochloride and doxorubicinone were kindly provided by Farmltalia Milan, Italy. Buffer substances and all other chemicals and solvents used were of regent grade." (Materials, p.74 "The purpose of this study was to provide information about the kinetics of hydrolysis of doxorubicin in acidic solution." (Introduction, p.74) "In 0.01-0.5M hydrochloric acid solutions (pH 0.4-2.1)." (Results and discussion, p.75). See also, Fig. 2, p.75 showing first-order hydrolysis reaction plots in 0.1 and 0.5M hydrochloric acid.

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,

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wherein said solution is contained in a sealed container

"The reaction solutions were kept in a thermostatically controlled water bath (±0.3°C) in screw-capped tubes protected from light and the reactions were initiated by dissolving a weighted quantity of doxorubicin hydrochloride in the pre-heated buffer solution to give an initial concentration of about 1.2 p.g* ml'1.'' (Kinetic Measurements, p.75)(emphasis added).

Limitations from Asserted Claim 12 A physiologically acceptable solution of

1983 Wassermann & Bundgaard reference "Samples of doxorubicin hydrochloride and doxorubicinone were kindly provided by Farmltalia Milan. Italy. Buffer substances and all other chemicals and solvents used were of reagent grade." (Materials, p.74) "Furthermore, knowledge about the acidstability may be useful to assess the extent of possible degradation of the drug in the stomach after oral administration." (Introduction, p.74)

anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride and epirubicin hyclrochloride

"Samples of doxorubicin hydrochloride and doxorubicinone were kindly provided by Farmltalia Milan, Italy. Buffer substances and all other chemicals and solvents used were of reagent grade." (Materials, p.74) "The purpose of this study was to provide information about the kinetics of hydrolysis of doxorubicin in acidic solution." (Introduction, p.74) "In 0.01-0.5M hydrochloric acid solutions (pH 0.4-2.1)." (Results and discussion, p.75). See also, Fig. 2, p.75 showing first-order hydrolysis reaction plots in 0.1 and 0.5M hydrochloric acid

dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

with a physiologically acceptable acid, wherein the physiologically acceptable acid is hydrochloric acid,

wherein said solution is contained in a sealed container

"The reaction solutions were kept in a thermostatically controlled water bath (±0.3°C) in screw-capped tubes protected from light and the reactions were initiated by 12

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dissolving a weighted quantity of doxorubicin hydrochloride in the pre-heated buffer solution to give an initial concentration of about 1.2 p.g*ml "1.''(Kinetic Measurements, p.75)(emphasis added).

Limitations from Asserted Claim 13
r-l,' _ .... 0 .... J .... _u,_ ..,u_..tu.tx u.t

1983 Wassermann & Bundgaard reference
o_aJtl:tl._l_.,_ UVak31UULS._Ill V.t IIyUIUI,_IIILIIIId_ i;tllld

doxorubicinone were kindly provided by Farmltalia Milan. Italy. Buffer substances and all other chemicals and solvents used were of reagent grade." (Materials, p.74) "Furthermore, knowledge about the acidstability may be usefut to assess the extent of possible degradation of the drug in the stomach after oral administration." (Introduction, p.74) dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 "The purpose of this study was to provide information about the kinetics of hydrolysis of doxorubicin in acidic solution." (Introduction, p.74) "In 0.01-0.5M hydrochloric acid solutions (.pH 0.4-2.1)." (Results and discussion, p.75). See also, Fig. 2, p.75 showing first-order hydrolysis reaction plots in 0.1 and 0.5M hydrochloric acid. wherein said solution is contained in a sealed container "The reaction solutions were kept in a thermostatically controlled water bath (_-0.3°C) in screw-capped tubes protected from light and the reactions were initiated by dissolving a weighted quantity of doxorubicin hydrochloride in the pre-heated buffer solution to give an initial concentration of about 1.2 p.g*mll. '' (Kinetic Measurements, p.75)(emphasis added).

with a physiologically acceptable acid, wherein the physiologically acceptable acid is hydrochloric acid,

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INTERROGATORY

NO. 13

With regard to the April 1980 Mori et al. reference, (i) identify with specificity each and every limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation. RESPONSE TO INTERROGATORY Limitations from Asserted Claim 9 NO. 13 April 1980 Mori et al. reference (Englishlanguage translation) "The buffer solutions and solvents used for the dissolution and dilution of ACM-HCI were prepared by dissolving high-grade reagents in distilled water for injection." (Experimental method, p.466) "In order to compare the stabilities of ACMHC1 based on the type of solvent used, sample solutions were prepared by dissolving ACMHC1 using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours at 37°C were measured. The results are shown in Table 5. (Stability of ACM-HC1 in various solvents, p.469) (emphasis added) dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 "In order to compare the stabilities of ACMHCI based on the type of solvent used, sample solutions were prepared by dissolving ACMHC1 using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours at 37°C were measured. The results are shown in Table 5. (Stability of ACM-HC1 in various solvents, p.469)(emphasis added) with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, "In order to compare the stabilities of ACMHC1 based on the type of solvent used, sample solutions were prepared by dissolving ACMHC1 using various pH 4.5 buffers, physiological saline, a 5% glucose solution, 14

A physiologically

acceptable solution of

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and distilled water for injection and adjusting the pH to 4.5 with O.01 N hydrochloric acid, and the residual potency levels after96 hours at 37°C were measured. The results are shown in Table 5. Slight differences in potency residual rates were observed based on the type of solvent used, and it was determined that the compound ·_,,_ ..... ,,,=,,== o,,a=x;wtxe, c]_'ate or v,,=j x acetate buffers are used." (Stability of ACMHCI in various solvems, p.469)(emphasis

added)
the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml, "ACM-HCL: Dissolved in each solvent to 2 mg (potency)/ml, and then adjusted to pH 4.5 and left for 4 days at 37°C '' (Footnote to Table 5, Experimental Results, p.468,) "The ACM-HCI bulk powder was dissolved to form a specific concentration, and I0 ml of the solution was dispensed into 15 ml clear vials. After isobutylene-isoprene rubber stoppers were placed on the vials, the vials were seamed and used as samples." (pH and thermal stability study, p.466)(emphasis added) See Table 5 data (Experimental Results, p. 469). "Based on this result [Arrhenius values], the time periods required to achieve a 10% potency decrease when the ACM-HC1 aqueous solution (pH 4.5) was stored at 5, 10, and 20°C were calculated to be 12, 6, and 1.5 months, respectively." (Experimental Results, p.469) "Because the ACM-HC1 aqueous solution is most stable around pH 4.5, the stability was studied using ACM-HC1 aqueous solutions with pH 4.5." (Discussion, p.470)

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 pH range using said acids.

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Limitations from Asserted Claim 11 A physiologically acceptable solution of

April 1980 Mori et al. reference "The buffer solutions and solvents used for the dissolution and dilution of ACM-HCI were prepared by dissolving high-grade reagents in distilled water for injection." (Experimental method, p.466) "In order to compare the stabilities of ACMHCI based on the type of solvent used, sample solutions were prepared by dissoNing ACMHCI using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours at 37°C were measured. The results are shown in Table 5. (Stability of ACM-HC1 in various solvents, p.469)(emphasis added)

dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

"In order to compare the stabilities of ACMHC1 based on the type of solvent used, sample solutions were prepared by dissolving ACMHCI using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours at 37°C were measured. The results are shown in Table 5. (Stability of ACM-HC1 in various solvents, p.469)(emphasis added)

with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid,

"Because the solubility of ACM-HC1 in water dramatically decreases at pH levels of 7 or greater, the experiment was performed in the range of pH 2 to 6." (Experimental Results, pH stability, p.466) "In order to compare the stabilities of ACMHC1 based on the type of solvent used, sample solutions were prepared by dissolving ACMHCI using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours 16

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at 37°C were measured. The results are shown in Table 5. Slight differences in potency residual rates were observed based on the type of solvent used, and it was determined that the compound degrades relatively easily when citrate or acetate buffers are used." (Stability of ACMHCI in various solvents, p.469)(emphasis
_uueu)

wherein said solution is contained in a sealed container

"The ACM-HC1 bulk powder was dissolved to form a specific concentration, and 10 ml of the solution was dispensed into 15 ml clear vials. After isobutylene-isoprene rubber stoppers were placed on the vials, the vials were seamed and used as samples." (pH and thermal stability study, p.466)(emphasis added)

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Limitations from Asserted Claim 12 A physiologically acceptable solution of

April 1980 Mori et aL reference "The buffer solutions and solvents used for the dissolution and dilution of ACM-HC1 were prepared by dissolving high-grade reagents in distilled water for injection." (Experimental method, p.466) "In order to compare the stabilities of ACMr-l_l based nn th_ typP nF _r_l,rpr_t 11_rl _2m,_l,, solutions were prepared by dissolving ACMHC1 using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled waterfor injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours at 37°C were measured. The results are shown in Table 5. (Stability of ACM-HCI in various solvents, p.469)(emphasis added)

dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

"In order to compare the stabilities of ACMHC1 based on the type of solvent used, sample solutions were prepared by dissolving ACMHCI using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours at 37°C were measured. The results are shown in Table 5. (Stability of ACM-HC1 in various solvents, p.469)(emphasis added) "Because the solubility of ACM-HC1 in water dramatically decreases at pH levels of 7 or greater, the experiment was performed in the range of pH 2 to 6." (Experimental Results, pH stability, p.466)

wi_ha physiologically acceptable acid, wherein the physiologically acceptable acid is hydrochloric acid,

"In order to compare the stabilities of ACMHC1 based on the type of solvent used, sample solutions were prepared by dissolving ACMHC1 using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours 18

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at 37°C were measured. The results are shown in Table 5. Slight differences in potency residual rates were observed based on the type of solvent used, and it was determined that the compound degrades relatively easily when citrate or acetate buffers are used." (Stability of ACMHCI in various solvents, p.469)(emphasis added) wherein said solution is contained in a sealed container "The ACM-HC1 bulk powder was dissolved to form a specific concentration, and 10 ml of the solution was dispensed into 15 ml clear vials. After isobutylene-isoprene rubber stoppers were placed on the vials, the vials were seamed and used as samples." (pH and thermal stability study, p.466)(emphasis added)

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Limitations from Asserted Claim 13 A physiologically acceptable solution of

April 1980 Mori et aL reference "The buffer solutions and solvents used for the dissolution and dilution of ACM-HC1 were prepared by dissolving high-grade reagents in distilled water for injection." (Experimental method, p.466) "In order to compare the stabilities of ACMI--l("l h.e,_d r_n *h,_ h_,_ ,-,,£ e.h,,.._, _,o,.A c,Q.t..,_.,.da

solutions were prepared by dissolving ACMHC1 using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours at 37°C were measured. The results are shown in Table 5. (Stability of ACM-HCI in various solvents, p.469)(emphasis added)

dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

"In order to compare the stabilities of ACMHC1 based on the type of solvent used, sample solutions were prepared by dissolving ACMHCI using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01 N hydrochloric acid, and the residual potency levels after 96 hours at 37°C were measured. The results are shown in Table 5. (Stability of ACM-HCI in various solvents, p.469)(emphasis added) "Because the solubility of ACM-HC1 in water dramatically decreases at pH levels of 7 or greater, the experiment was performed in the range of pH 2 to 6." (Experimental Results, pH stability, p.466)

with a physiologically acceptable acid, wherein the physiologically acceptable acid is hydrochloric acid,

"In order to compare the stabilities of ACMHC1 based on the type of solvent used, sample solutions were prepared by dissolving ACMHC1 using various pH 4.5 buffers, physiological saline, a 5% glucose solution, and distilled water for injection and adjusting the pH to 4.5 with 0.01N hydrochloric acid, and the residual potency levels after 96 hours 20

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at 37°C were measured. The results are shown in Table 5. Slight differences in potency residual rates were observed based on the type of solvent used, and it was determined that the compound degrades relatively easily when citrate or acetate buffers are used." (Stability of ACMHC1 in various solvents, p.469)(emphasis added) wherein said solution is contained in a sealed container "The ACM-HC1 bulk powder was dissolved to form a specific concentration, and 10 ml of the solution was dispensed into 15 ml clear vials. After isobutylene-isoprene rubber stoppers were placed on the vials, the vials were seamed and used as samples." (pH and thermal stability study, p.466)(emphasis added)

INTERROGATORY

NO. 14

With regard to the May 1980 Mori et al. reference, (i) identify with specificity each and every limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation.

21

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RESPONSE TO INTERROGATORY NO. 14 Limitations from Asserted Claim 9 dissolved in a physiologically acceptable aqueous solvent, having a pH adjustedto from 2.5 to 5.0 May 1980 Mori et aL reference "The pH stability of ACM-HC1 was measured at the concentrationof 2 mg/ml in 0.1 M phosphate-citrate buffer at 37°C. As shown in Fig. 4, it was found that ACM-HCI in the various pH solutions was inactivated with an
C, LIJIJ_J._J.LI, L_tLOI,--UL_J._,.L LVCI._I.LUJ.L. J. Ii_ Lr_LCI, LIULISIUIJ

between pH and logarithm of k (degradation constant; hr) indicated that ACM-HC1 was most stable in the pH range between 4 and 5." (Stability of ACM-HCI, p.621).

with a physiologically acceptable acid selected "The pH stability of ACM-HC1 was measured from the group consisting of hydrochloric acid, at the concentration of 2 mg/ml in 0.1 M sulfuric acid, phosphoric acid, methane phosphate-citrate buffer at 37°C. As shown in sulfonic acid, and tartaric acid, Fig. 4, it was found that ACM-HC1 in the various pH solutions was inactivated with an apparent fn'st-order reaction. The relationship between pH and logarithm of k (degradation constant; hr) indicated that ACM-HC1 was most stable in the pH range between 4 and 5." (Stability of ACM-HCI, p.621)(emphasis added).

the concentration of said anthracycline glycoside being from 0.1 to 100 mg/ml,

"The stability of ACM-HCI in the solid state and in solution was studied by the change in potency, pH (5 mg/ml in water) and appearance." (Stability of ACM-HC1, p.620) "The pH stability of ACM-HCI was measured at the concentration of 2 mg/ml in 0.1 M phosphate-citrate buffer at 37°C. As shown in Fig. 4, it was found that ACM-HC1 in the various pH solutions was inactivated with an apparent first-order reaction. The relationship between pH and logarithm of k (degradation constant; hr) indicated that ACM-HC1 was most stable in the pH range between 4 and 5." (Stability of ACM-HC1, p.621).

wherein said solution is contained in a sealed

It necessarily follows from good laboratory practice and simple common sense, and thus 22

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container

would be understood by one skilled in the art, [ that the containers and conditions disclosed in Mori were sealed to avoid contamination, evaporation, and dangerous exposure of the researchers to doxorubiein, which is a highly cytotoxic agent that requires extreme care in handling.

_t_Ulilty

[i-lJ

III_W

u_iuttunor

matrtracyclme

anHD1OUC

as a result of said pH being adjusted to the said pH range using said acids.

aclacinomycin A (ACM) was isolated from Streptomyces galilaeus. In this paper, the physicochemical properties and stability of ACM hydroehloride (ACM-HC1) are described." (Abstract, p.618). "The pH stability of ACM-HC1 was measured at the concentration of 2 mg/ml in 0.1 M phosphate-citrate buffer at 37°C. As shown in Fig. 4, it was found that ACM-HC1 in the various pH solutions was inactivated with an apparent first-order reaction. The relationship between pH and logarithm of I_(degradation constant; hr) indicated that A CM-HCI was most stable in the pH range between 4 and 5." (Stability of ACM-HC1, p.621)(emphasis added).

Limitations from Asserted Claim 11 dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

May 1980 Mori et aL reference "The pH stability of ACM-HC1 was measured at the concentration of 2 mg/ml in 0.1 M phosphate-citrate buffer at 37°C. As shown in Fig. 4, it was found that ACM-HCI in the various pH solutions was inactivated with an apparent first-order reaction. The relationship between pH and logarithm of k (degradation constant; hr) indicated that ACM-HC1 was most stable in the pH range between 4 and 5." (Stability of ACM-HCI, p.621). "The pH stability of ACM-HC1 was measured at the concentration of 2 mg/ml in 0.1 M phosphate-citrate buffer at 37°C. As shown in Fig. 4, it was found that ACM-HCI in the various pH solutions was inactivated with an l 23

with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid,

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apparent first-order reaction. The relationship between pH and logarithm of k (degradation constant; hr) indicated that ACM-HC1 was most stable in the pH range between 4 and 5." (Stability of ACM-HC1, p.621)(emphasis added).

wherein said solution is contained in a sealed Ct3ntMn_r ........

It necessarily follows from good laboratory practice and _:--'^ _-x._,z_common sense, _ta"_uiu_ -- "-would be understood by one skilled in the art, that the containers and conditions disclosed in Moil were sealed to avoid contamination, evaporation, and dangerous exposure of the researchers to doxorubicin, which is a highly cytotoxic agent that requires extreme care in handling.

Limitations from Asserted Claim 12 dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

May 1980 Mori et aL reference "The pH stability of ACM-HCI was measured at the concentration of 2 mg/ml in 0.1 M phosphate-citrate buffer at 37°C. As shown in Fig. 4, it was found that ACM-HCI in the various pH solutions was inactivated with an apparent first-order reaction. The relationship between pH and logarithm of k (degradation constant; hr) indicated that ACM-HC1 was most stable in the pH range between 4 and 5." (Stability of ACM-HC1, p.621). It necessarily follows from good laboratory practice and simple common sense, and thus would be understood by one skilled in the art, that the containers and conditions disclosed in Mori were sealed to avoid contamination, evaporation, and dangerous exposure of the researchers to doxorubicin, which is a highly cytotoxic agent that requires extreme care in handling.

wherein said solution is contained in a sealed container

24

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Limitations from Asserted Claim 13 dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0

May 1980 Mori et aL reference "The pH stability of ACM-HCI was measured at the concentration of 2 mg/ml in 0.1 M phosphate-citrate buffer at 37°C. As shown in Fig. 4, it was found that ACM-HCI in the various pH solutions was inactivated with an apparent first-order reaction. The relationship between pH and logarithm ofk (degradation
_4_4-. _,'U.tJ._,I.GIIL, '[,_.'1 ;_,.-Z:^^,¢,.^.,I 111,./ 111UlI,..,_tL[;U .1-I.^* UIU.L /,, t'ai ,41" TTI"_I ,t_..,ZVl-1-'l_...1 ..... WU_

most stable in the pH range between 4 and 5." (Stability of ACM-HC1, p.621). wherein said solution is contained in a sealed container It necessarily follows from good laboratory practice and simple common sense, and thus would be understood by one skilled in the art, that the containers and conditions disclosed in Mori were sealed to avoid contamination, evaporation, and dangerous exposure of the researchers to doxorubicin, which is a highly cytotoxic agent that requires extreme care in handling.

INTERROGATORY NO. 15 With regard to the 1972 Arcamone et al. reference, (i) identify with specificity each and every limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation. RESPONSE TO INTERROGATORY Limitations from Asserted Claim 9 A physiologically acceptable solution of NO. 15 1972 Arcamone et aL reference See Table 2, p.20, which discloses various physiologically acceptable solutions See Table 2, p.20, which discloses the stability of adriamycin hydrochloride (a/Ma doxorubicin hydrochloride).

anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride and epirubicin hydrochloride

25

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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 coneentratinn nf _icl Anfhrnc'volln_

See Table 2, p.20, which discloses physiologically acceptable aqueous solvents having pH adjusted to from 1 to 8. Table 2, p.20 reports data using hydrochloric acid, phosphate buffer at pH 3-6, which would necessarily include phosphoric acid especially at the pH 3 end of this range.
T_hi_, 9 n ')fl ranr,_l-e r,,-,nt, a,,_-,-o._ .... _cf_ N_;

glycoside being from 0.1 to 100 mg/ml, Wherein said solution exhibits storage stability as a result of said pH being adjusted to the said pH range using said acids.

mg/ml to 2 mg/ml. Table 2, p.20 reports stability in excess of 1 month for pH 3-6.

Limitations from Asserted Claim 11 A physiologically acceptable solution of

1972 Arcamone et aL reference See Table 2, p.20, which discloses various physiologically acceptable solutions See Table 2, p.20, which discloses the stability of adriamycin hydrochloride (a/k/a doxorubicin hydrochloride).

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 physiologically acceptable acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, and tartaric acid, wherein the concentration of anthracycline glycoside is about 1 mg/ml

See Table 2, p.20, which discloses physiologically acceptable aqueous solvents having pH adjusted to from 1 to 8 Table 2, p.20 reports data using hydrochloric acid, phosphate buffer at pH 3-6, which would necessarily include phosphoric acid especially at the pH 3 end of this range. Table 2, p.20 reports concentrations of 0.05 mg/ml to 2 mg/ml.

26

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Limitations from Asserted Claim 12 A physiologically acceptable solution of

1972 Arcamone et aL reference See Table 2, p.20, which discloses various physiologically acceptable solutions. See Table 2, p.20, which discloses the stability of adriamycin hydrochloride (a/k/a doxorubicin hydrochloride).

anthracycline glycoside selected from the group consisting of idarubicin hydrochioride, doxorubicin hydrochioride 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, wherein the physiologically acceptable acid is hydrochloric acid, wherein the concentration of anthracycline glycoside is about 1 mg/ml

See Table 2, p.20, which discloses physiologically acceptable aqueous solvents having pH adjusted to from 1 to 8. Table 2, p.20 reports data using hydrochloric acid.

Table 2, p.20 reports concentrations of 0.05 mg/ml to 2 mg/ml.

Limitations from Asserted Claim 13 A physiologically acceptable solution of

1972 Areamone et al. reference See Table 2, p.20, which discloses various physiologically acceptable solutions. See Table 2, p.20, which discloses physiologically acceptable aqueous solvents having pH adjusted to from 1 to 8. Table 2, p.20 reports data using hydrochloric acid. Furthermore, one of ordinary skill in the art would recognize that phosphate buffered at pH 3 could be adjusted with HC1. Table 2, p.20 reports concentrations of 0.05 mg/ml to 2 mg/ml.

dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 with a physiologically acceptable acid, wherein the physiologically acceptable acid is hydrochloric acid,

Wherein the concentration of said anthracycline glycoside is 1 mg/ml,

INTERROGATORY

NO. 16

With regard to the 1979 Hoffman et al. reference, (i) identify with specificity each and every limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation. 27

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RESPONSE TO INTERROGATORY NO. 16 The 1979 Hoffman et al. reference reports the analysis of the lyophilized form of doxorubicin hydrochloride solvated in Water for Injection to a concentration of 2 rag/m1. Consequently, although 1979 Hoffman discloses a physiologically acceptable solution of an anthracycline glycoside (i.e. doxorubicin hydrochloride) because Hoffman uses an anthracycline glycoside reconstituted from a lyophilizate this reference is not applied on an element by element basis. Hoffrnan et al. specifically teaches that the solution is storage stable, thereby motivating a person of ordinary skill in the art to pursue formulation conditions with even greater stability based upon the teachings of related prior art. INTERROGATORY NO. 17 With regard to the 1981 Ketchum et al. reference, (i) identify with specificity each and every limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation. RESPONSE TO INTERROGATORY NO. 17 The 1981 Ketchum et al. reference reports the analysis of the lyophilized form of doxorubicin hydrochloride solvated in 0.9% NaC1 solution to a concentration of 2 mg/ml. Consequently, although 1981 Ketchum reference discloses a physiologically acceptable solution of an anthracycline glycoside (i.e. doxorubicin hydrochloride) because Ketchum uses an anthracycline glycoside reconstituted from a lyophilizate this reference is not applied by Sicor on an element by element basis. Ketchum et al. specifically teaches that the solution is storage stable, thereby motivating a person of ordinary skill in the art to pursue formulation conditions with even greater stability based upon the teachings of related prior art.

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INTERROGATORY NO. 18 With regard to the 1981 Poochikian et al. reference, (i) identify with specificity each and eve_, limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation. RESPONSE TO INTERROGATORY NO. 18

The 1981 Poochikian et al. reference reports the stability analysis of the lyophilized form of several anthracycline glycosides (including doxorubicin hydrochloride and ACM-HC1) solvated in various standard infusion fluids. Consequently, although the 1981 Poochikian reference discloses a physiologically acceptable solutions of two anthracycline glycosides, including doxorubicin hydrochloride, because Poochikian uses an anthracycline glycoside reconstituted from a lyophilizate this reference is not applied by Sicor on an element by element basis. Poochikian et al. specifically teaches that anthracycline glycosides such as doxombicin HC1 and aclacinomycin A HC1 display similar storage stability characteristics, thereby motivating a person of ordinary skill in the art to pursue formulation conditions having similar stability characteristics based upon the teachings of related prior art. INTERROGATORY NO. 19 With regard to the 1980 Vigevani & Williamson reference, (i) identify with specificity each and every,limitation of the asserted claims that is allegedly taught in the reference, and (ii) for each such limitation, identify with specificity how and where the reference teaches such limitation. RESPONSE TO INTERROGATORY NO. 19

On Page 263 of the 1980 Vigevani & Williamson reference there is disclosure of a physiologically acceptable solution of an anthracycline glycoside selected from the group consisting of idarubicin hydrochloride, doxorubicin hydrochloride and epirubicin hydrochloride 29

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dissolved in a physiologically acceptable aqueous solvent, having a pH adjusted to from 2.5 to 5.0 wherein said solution exhibits storage stability as a result of said pH being adjusted to the said pH range, in particular, i 980 Vigevarti & Williamson discloses doxorubicin and doxorubicin hydrochloride. ,/ Dated: / Respectfully submitted,

'/( _ [ "_ OO _-

/ SCHEIN NATH & ROSENTHAL LLP e /xM--"_orJ_an . Sigale A /

Reid L. Ashinoff David R. Baum SONNENSCHEIN NATH & ROSENTHAL LLP 1221 Avenue of the Americas New York, New York 10020 (212) 768-6700

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