CERTIFICATE OF ELECTRONIC TRANSMISSION UNOER 37 C.F.R. § 1.8
`
`Attomey Docket No. 23278.2
`PATENT
`
`J hereby cc•·tify that this correspondence, including any items indicated as attached or included, is
`'being transmitted via electronic transmission \~a EFS-Web on the date indicated below.
`
`Date: Ap.-il 6. 2009
`
`/Michelle D. Miller/
`Michelle D. Miller
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Jn re Application:
`
`Calderm·i, et al.
`
`Serial No.
`
`11/186,311
`
`Filed :
`
`July 21, 2005
`
`For: Liquid Pharmaceutical
`Formulations of Palonosetron
`
`)
`)
`) Examiner:
`)
`) At·t Unit:
`)
`)
`)
`)
`)
`
`Shirley V. Gcmbeh
`
`1614
`
`AMENDMENT AND RESPONSE TO OFFICE ACTION
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`
`Oeat· Sir:
`
`In response to the Office Action mailed in the above-referenced application on October
`6, 2008, please enter the following amendments and consider the following remarks.
`Enclosed herewith are the following documents:
`• Request is hereby made to extend the time for response to the Office Action of October
`6, 2008 to and through April 6, 2009, comprising an extension of the shortened period
`of Three M onths.
`• The 132 s t~;~.tutory declaration of Daniele Bonadeo.
`• The 132 statutory declaration of Valentino Stella.
`
`2587233v1
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1048
`
`Exh. 1048
`
`

`
`U.S.S.N . 111186,311
`Amendment and Response to O±l1ce Action
`April 6, 2009
`Page 2 of9
`
`Amendments to the claims begin on page 3. No new claims are presented. Claims 1-
`31, 35, 37, 38, 45. 47 and 51-79 are canceled. Claims 32, 39, 40, 41, and 42 are amended.
`After the amendments, claims 32-34, 36, 39-44, 46 and 48-50 are .pending. Claims 32 and 42
`are the only remaining independent claims. No new matter is added loy the amendments.
`Remarks begin on page 5.
`
`2587233v1
`
`Exh. 1048
`
`

`
`U .S.S.N. 11/186,311
`Amendment and Response to Office Action
`April 6, 2009
`Page 5 of9
`
`REMARKS
`The present claims are drawn towards pharmaceutically stable intravenous solutions of
`palonosetron. One of the key aspects of the claims in the requirement for a chelating agent.
`There is· nothing in the prior art that would have motivated a skilled worker to employ a
`cbelating agent such as EDTA in the formulation.
`In fact, the use of a cbclating agent to
`stabilize this formulation produces unexpected surprising results because Applicant's earlier
`work with palonosetron suggested that it would not benefit from a chelating agent. As stated
`in paragraph 16 of the Bonadeo declaration: "The fact that EDTA improves the stability of
`palonosetron at all is somewhat surprising, given our earliest work with the molecule, in which
`palonosetron demonstrated comparable stability at 5 oc as it did at 60-100 oc. If the molecule
`were undergoing auto-oxidation (the typical reason for adding a l:hdatir1g agent), one would
`expect the higher temperature to produce more radical initiators and a faster reaction and
`degradation." This is the exact same conclusion that Dr. Stella reached in paragraphs 15-17 of
`his declaration that was filed on January 9, 2009. There is nothing about palonosetron that
`suggests it would have benefitted from a chelating agent, or that would have motivated a
`skilled worker to use a chelating agent.
`The Office Action states that tbe citric acid in the Berger '333 patent examples is a
`chelating agent, and that it it would have been obvious to use EDTA instead of the citric acid
`described in the Berger '333 examples. However, this argument assumes that Berger was
`using citric acid as a chelating agent when he most likely was using the citric acid to adjust the
`pH of lht! sulutiou. As Dr. Stella explaius in paragraph 10 of his declaration, the prior art docs
`not teach that a chelating agent should be used with palonosetron because palonosetron "lacks
`any of the structural features that commonly favor structural degradation."
`There is also nothing in the prior art that would have motivated a skilled worker to
`work with the low concentrations of palonosetron described in the claims. In fact, there are
`two surprising results associated w ith this low palonosetron concentration:
`The fact that palonosetron becomes more stable as its concentration
`(1)
`decreases is surprising, as explained hy Dr. Stella in paragraph 16 of his declaration, because
`
`258i233v1
`
`Exh. 1048
`
`

`
`U.S.S.N. ll/18G,31l
`Amendment and Response to Office Action
`Aptil 6, 2009
`Page 6 of9
`
`auto-oxidation reactions typically become more favorable as tbe palonosetron concentration is
`reduced;
`The fact that the chelating agent only works at th e lower concentrations of
`(2)
`palonosetron described in the claims is also surprising. There is apparently a synergistic
`relationship between the use of a chelating agent and palonosetron, that only exists at the low
`concentrations described in the claims. As stated in paragraph 15 of the Bonadeo declaration,
`"One notable obsenation from these results is that the presence of EDTA improves stability at
`low palonosetron concentrations, but actually decreases stability at high palonosetron HCl
`concentrations." The main prior art cited against this application is the Berger. '333 patent,
`which describes formulations that have higher concentrations of palonosetron. The fact that a
`chelating agent does not stabilize palonosetron at the higher concentrations taugot in the Berger
`'333 patent, but that it dues at the wncentralions claimed in this application, further supports
`the patentability of the present invention.
`The Bonadeo declaration also presents evidence of the unexpected stabilizing effect of
`pH on the formulation. See Bonadeo declaration at par. "lO and Table 2.
`
`TABLE 2. Palonosetron HCI 80 °C piT-Stability Study
`
`pH at Room
`Temp.
`2.0
`5.0 .
`
`pH at Reaction
`Temp.
`2.0
`5.0
`
`Buffer
`
`O.O l. M HCI
`Acetate
`
`7.4
`10
`
`7.3
`9.4
`
`Phosphate
`Carbonate
`
`T9o
`(days)
`76
`Not determined.
`99.2% remaining at
`25_2 days
`180
`270
`
`Again, this could not have been predicted from the Berger '333 formulation, which had a pH
`of 3. 7. See Bonadeo Dec. at Table 5.
`Finally, Claim 41 and 42 are now limited to a very specific formulatio n, based on the
`showing in paragraphs 20 and 21 of the attached declaration from Daniele Bonadeo. That
`declaration presents the foJlowing figure 2:
`
`2587233v1
`
`Exh. 1048
`
`

`
`U.S.S.N. 111186,311
`Amendment and R~ponse to Office Action
`April 6, 2009
`Page 7 of9
`
`2 0
`
`40
`bui i .,,.
`
`6 0
`
`eo
`
`Figure 2
`"at the low palonosetron
`As explained in paragraph 21 of the Bonadeo declaration:
`concentration depicted, there is a region of no apparent degradation with EDTA from 0.025 to
`0 .075 % w/v and buffer from 10 tO 40 mM. This region is marked by the ~ symbol."
`The formulation recited in claim 1 is limited to the region marked by a 19 symbol in
`Figure 2, and is .almost exactly the same as the formulation shown in this figure, as the
`following table demonstrates:
`Formulation of Claim 1
`
`Citrate buffer 10-40 millimoles
`EDT A 0.3-0.7 mg/ml
`
`Mannitol tonicifying agent
`pH 4.0-6.0
`Palonosetron 0.03-0.2 mg/ml
`
`Figure 2 FormulatiQn; region d euotcd
`by ~ symbol
`Citrate buffer 10-40 rnilbmoles
`EDTA 0.025-0.075% w/v (i.e. 0.25-0.75
`mg/ml)
`Mannitol tonicifying agent
`pHS.O
`Palonosetron hydrochloride 0.4 mg(ml
`
`Nothing in the prior art would have motivated a skilled worker to employ a citrate
`huffer and EDTA in the proportions described in claim 1. In fact, these proportions exhibit
`unexpected surprising results. It could not have been predicted that the combination of EDT A
`and buffer concentrations in the ~ region would ·produce th~ most stable formulation,
`especially in a formulation having a pH of 4-6, mannitol as the tonicifying agent, and a
`palonosetron concentration of 0.03-0.2 mg/ml
`
`2587233v1
`
`Exh. 1048
`
`

`
`U.S.S.N. 111186,311
`Amendment and Response to Office Action
`April 6, 2009
`P age 8 of9
`
`Finally, the Bonadeo declaration includes comparative data in cable 5, comparing the
`predicted stability of the Berger '333 formulation and the claimed for mulation in table 5 of the
`Bonadeo declaration. That table is reproduced below:
`
`TABLES
`
`Ber ger '333 Example 13
`Intravenous Fornmlation
`10- l OOmg *
`
`Palonosctron
`H_ydrocbloride
`3.7
`pH
`Dextrose monohydrate
`q.s. to render isotonic
`tonicifying agent
`Mannitol tonicifYing agent --
`Citric acid monohydrate
`1.05 mg
`O.l81ng
`Sodium h ydroxide**
`EDTA
`--
`--
`Trisodium citrate
`Water for injection
`q.s. to LO ml
`
`Example 4 of Present
`Application
`0.05 mg
`
`5.0
`--
`
`-
`
`41..5 mg/ml
`1.56 mg
`q.s . to pH 5.0 ± 0.5
`0.5 mg
`3.7mg
`q.s. to 1.0 ml
`
`·-·
`
`1-2 Year Stability'!
`
`NO**"''
`
`YES
`
`*Assuming compound of fomlUla I in Example 13 is palonosetron
`**Assumes fommlation requires pH increase
`*** Predicted
`
`As can be seen, the fonnulations ofthe present invention are pharmaceutically stable, when_the
`formulations described in the Berger '333 patent most likely are not. Once again, this data is
`surprising and unexpected, and supports the patentability of the claimed invention.
`
`CONCLUSION
`
`Based on th e foregoing amendments, Applicant re~pectfully submits that this application
`is in condition for allowance and earnestly solicits prompt notice of same. Should the Examiner
`have any questions or concerns regarding this application, he is invited to contact the
`
`2587233v1
`
`Exh. 1048
`
`

`
`U.S.S.N. 111186,311
`Amendment and Response to Office Action
`April 6, 2009
`Page 9 of9
`
`undersigned at 404-873-8512. To the extent any fees are due for this submission, the
`Commissioner is authorized to charge deposit account number 012506.
`
`Respectfully submitted,
`
`Clark G . Sullivan
`Reg. No. 36,942
`
`Arnall Golden Gregory LLP
`171 17111 Street NW
`Suite 2 100
`Atlanta, Georgia 30363
`404 .. 873.8512
`AGG Docket: 23278.2
`
`25ll7233vl
`
`Exh. 1048