LN THE UNITED STATES PATENT AND TRADEMARK OFFLCE
`
`In reApplication of:
`Duncan et al.
`
`Examiner: Lyndsey Beckhardt
`
`Application No.: 11/788,076
`
`TC/Art Unit: 4121
`
`Filed: April 18, 2007
`
`Confirmation No.: 4752
`
`Title: PRE-MIXED, READY TO USE
`PHARMACEUTICAL COMPOSITIONS
`
`Attorney Docket Number: 19015-63
`
`Date: July 6, 2009
`
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Amendment and Interview Summary
`
`Sir:
`
`This communication is being filed in response to the April 10, 2009 Office Action issued
`
`in connection with the above-referenced application. A response to the Office Action is due July
`10, 2009. Accordingly, this response is being timely filed.
`
`Amendments to the Claims are reflected in the Listing of Claims which begins on page
`2 of this paper.
`
`Remarks begin on page 6 of this paper.
`
`190U/63
`07/06/2009 11929026.1
`
`Sandoz Exhibit 1017 Page 1
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`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`1.
`
`Amendments to the Claims
`
`This listing of claims shall replace all prior versions, and listings, of claims in the
`application.
`Listing of Claims
`
`1-39. (Canceled)
`
`40. (Currently Amended) A pharmaceutical composition for parenteral administration
`
`comprising a pre-mixed aqueous solution with a pH from about 3.6 to about 4. 7 comprising:
`
`from about 0.1 to 0.4 mg/mL nicardipine hydrochloride;
`
`a tonicity agent selected from (i) about 4.5% to about 5% dextrose or (ii) about
`
`0.8% to about 0.9% sodium chloride; and
`
`a buffer in an amount to maintain pH from about 3.6 to about 4.7 frem aaetlt 9.01
`
`te abe~;~t 9.1 mWmL eitrie aeiEI;
`
`the aqueous solution contained in a pharmaceutically acceptable container such
`
`that the solution does not come into contact with polar polymers;
`
`the aqueous solution when stored in the container for at least one year at room
`
`temperature exhibiting (i) Jess than a 10% decrease in the concentration of nicardipine
`
`hydrochloride and (ii) a total impurity formation of less than about 3%.
`
`41. (Previously Presented) The composition of claim 40, further comprising at least one
`
`pH adjuster selected from the group consisting of hydrochloric acid, sodium hydroxide and a
`
`mixture thereof.
`
`42. (Previously Presented) The composition of claim 40, further comprising from about 1
`
`mglml to about 4 mg/ml sorbitol.
`
`Sandoz Exhibit 1017 Page 2
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`

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`Appl. No. 111788,076
`Amendment dated July 6, 2009
`
`43. (Previously Presented) The composition of claim 40, wherein the container comprises
`
`copolyester, polyethylene or polyolefin.
`
`44. (Currently Amended) A pharmaceutical composition for parenteral administration
`
`comprising a pre-mixed aqueous solution with a pH from about 3.6 to about 4.7 comprising:
`
`from about 0.1 to about 0.2 mglmL nicardipine hydrochloride;
`
`a tonicity agent selected from (i) about 46 to about 50 mg/mL dextrose or (ii)
`
`about 8.3 to about 9 mg/mL sodium chloride; and
`
`a buffer in an amount to maintain pH from about 3.6 to about 4.7 from about
`
`0.0192 to about 0.0384 mglmL eitrie aeid;
`
`the aqueous solution contained in a pharmaceutically acceptable container
`
`comprising copolyester, polyethylene or polyolefin;
`
`the aqueous solution when stored in the container for at least one year at room
`
`temperature exhibiting (i) less than a 10% decrease in the concentration of nicardipine
`
`hydrochloride and (ii) a total impurity formation ofless than about 3%.
`
`45. (New) A pharmaceutical composition for parenteral administration comprising a pre(cid:173)
`
`mixed aqueous solution comprising:
`
`from about 0.1 to about 0.2 mglmL nicardipine hydrochloride;
`
`a tonicity agent selected from (i) about 46 to about 50 mg/mL dextrose or (ii)
`
`about 8.3 to about 9 mg/mL sodium chloride;
`
`from 0 mglmL to about 4 mg/mL sorbitol; and
`
`a buffer in an amount to maintain pH from about 3.6 to about 4.7~
`
`the aqueous solution contained in a pharmaceutically acceptable container
`
`comprising copolyester, polyethylene or polyolefin;
`
`-3-
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`Sandoz Exhibit 1017 Page 3
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`

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`Appl. No. 11/788,076
`Amendment dated July 6, 2009
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`the aqueous solution when stored in the container for at least one year at room
`
`temperature exhibiting (i) less than a 10% decrease in the concentration of nicardipine
`
`hydrochloride and (ii) a total impurity formation ofless than about 3%.
`
`\
`
`46. (New) A pharmaceutical composition for parenteral administration comprising a pre(cid:173)
`
`mixed aqueous solution comprising:
`
`from about 0.1 to about 0.2 mg/mL nicardipine hydrochloride;
`
`a tonicity agent selected from (i) about 46 to about 50 mg/mL dextrose or (ii)
`
`about 8.3 to about 9 mglmL sodium chloride;
`
`from 0 mg/mL to about 4 mg/mL sorbitol; and
`
`a buffer in an amount to maintain pH from about 3.6 to about 4.7;
`
`the aqueous solution' contained in a pharmaceutically acceptable container
`
`comprising copolyester, polyethylene or polyolefin.
`
`47. (New) The pharmaceutical composition for parenteral administration of claim 46,
`
`wherein the aqueous solution when stored in the container for three months at room temperature
`
`exhibits less than a 10% decrease in the concentration of nicardipine hydrochloride.
`
`48. (New) The pharmaceutical composition for parenteral administration of claim 46,
`
`wherein the aqueous solution when stored in the container for three months at room temperature
`
`exhibits a total impurity formation of less than about 3%.
`
`49. (New) The pharmaceutical composition for parenteral administration of claim 46,
`
`wherein the aqueous solution when stored in the container for one year at room temperature
`
`exhibits less than a 10% decrease in the concentration ofnicardipine hydrochloride.
`
`-4-
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`Sandoz Exhibit 1017 Page 4
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`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`50. (New) The pharmaceutical composition for parenteral administration of claim 46,
`
`wherein the aqueous solution when stored in the container for one year at room temperature
`
`exhibits a total impurity formation of less than about 3%.
`
`51. (New) The pharmaceutical composition for parenteral administration of claim 40,
`
`wherein the buffer is citric acid.
`
`52. (New) The pharmaceutical composition for parenteral administration of claim 44,
`
`wherein the buffer is citric acid.
`
`53. (New) The pharmaceutical composition for parenteral administration of claim 45,
`
`wherein the buffer is citric acid.
`
`54. (New) The pharmaceutical composition for parenteral administration of claim 46,
`
`wherein the buffer is citric acid.
`
`Sandoz Exhibit 1017 Page 5
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`

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`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`II.
`
`Remarks
`Status of the Claims
`A.
`Claims 40-54 will be pending after entry of this amendment. Claims 1-39 have been
`canceled without prejudice. Claims 40 and 44 have been amended without prejudice and new
`claims 45-54 have been added, with claims 45 and 46 being in independent form.
`
`Support for the amendments to claims 40 and 44 is found throughout the specification as
`originally filed, e.g., at page 6, paragraph 23.
`
`Support for new claims 45-54 is found throughout the specification as originally filed,
`e.g., at page 5, paragraph 21; page 9, paragraphs 31 and 32; page 6, paragraph 24; page 25,
`paragraph 87; and the original claims and figures.
`
`Applicants respectfully submit that no new matter has been added by virtue of the present
`amendments .
`
`. B.
`
`Summary oflnterview
`
`Applicants wish to thank Examiner Beckhardt and Examiner Jones for the courtesies
`extended in the June 9, 2009 Interview with Applicants' representative, Robert J. Paradiso and
`Dr. Harry Brittain. During the interview, the rejections in the Office Action and the cited
`references were discussed in view of the following positions:
`
`(i) there was no expectation of success in formulating a stable form of a low
`concentration drug as presently claimed;
`(ii) the prior art teaches away from certain embodiments of the invention; and
`(iii) the present invention meets a long felt need in the art.
`
`Also discussed were the new claims presented in the March 13, 2009 communication and
`a new proposed claim which has been incorporated in the present response as independent claim
`45. Applicants discussed cancelling claims 1-39 without prejudice in order to advance
`prosecution.
`
`Sandoz Exhibit 1017 Page 6
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`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`During the interview, exhibits of a concentrated nicardipine hydrochloride ampule
`
`product and a low concentration ready-to-use nicardipine hydrochloride product were shown to
`
`the Examiner.
`
`B.
`
`Claim Rejections Under 35 U.S.C. § 103
`
`1. The McFarlane Reference
`
`In the Office Action, claims 1-5,7-8,10, 14, 17-19,21-22,24-26 and 28-29 were rejected
`
`under 35 U.S. C. § 1 03(a) as being unpatentable over U.S. Patent No. 5,164,405 (the McFarlane
`
`reference).
`
`In order to advance prosecution, claims 1-5, 7-8, 10, 14, 17-19, 21-22, 24-26 and 28-29
`
`have been cancelled without prejudice.
`
`Accordingly, Applicants respectfully request that the rejection under 35 U.S.C. § l 03(a)
`
`over the McFarlane reference be removed.
`
`2. The McFarlane reference in view of the Gayed reference
`In the Office Action, claim 15 was rejected under 35 U.S.C. § 103(a) as being
`
`unpatentable over the McFarlane reference in view ofWOOl/07086 (the Gayed reference).
`
`ln order to advance prosecution, claim 15 has been cancelled without prejudice.
`
`Accordingly, Applicants respectfully request that the rejection under 35 U.S. C. § 103(a)
`
`over the McFarlane reference in view of the Gayed reference be removed.
`
`3. The McFarlane reference in view of the Kaiser reference
`
`In the Office Action, claims 16, 40-41 and 43-44 were rejected under 35 U.S.C. § l03(a)
`
`as being unpatentable over the McFarlane reference in view of Solutions to Health Care Waste:
`
`Life-Cycle Thinking and "Green' Purchasing (the Kaiser reference). Applicants note that claim
`
`16 has been cancelled.
`
`-7-
`
`Sandoz Exhibit 1017 Page 7
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`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`The rejections of claims 40-41 and 43-44 are respectfully traversed in view of the
`following remarks. Section (i) below discusses the benefits of the present invention, section (ii)
`discusses that there was no expectation of success in formulating a stable form of a low
`.
`concentration drug as presently claimed, and section (iii) discusses that the present invention
`
`meets a long felt need in the art. The Examiner is directed to the Declaration of Dr. Harry G.
`Brittain which accompanies this response.
`
`i. Benefits Of The Present Invention
`
`Nicardipine hydrochloride is a calcium channel blocker and based on its FDA approved
`labeling is indicated for the treatment of acute elevations of hypertension.
`
`Prior to the filing date of the present application, injectable nicardipine hydrochloride
`was commercially available solely in a concentrated form, being first approved by the FDA in
`
`1992. The concentrate formulation is packaged in a glass ampule and requires reconstitution
`prior to being administered to a patient.
`
`As explained in the accompanying Declaration by Dr. Harry G. Britain, the concentrated
`ampule formulations ofnicardipine hydrochloride present a number of issues for patients and
`health care professionals including:
`
`The requirement of dilution can result in a lag time that prevents a patient in an acute
`setting from receiving the drug in a timely fashion. From Dr. Brittain's experience
`working in the pharmaceutical industry, he states that after an order is written by a
`physician in a hospital setting, it can sometimes take up to 2 hours or longer for the
`reconstituted product to be available to the patient. This results in the health care
`professional facing the choice of either a dangerous delay in administration of a
`potentially life-saving therapeutic agent, or replacing the preferred formulation with a
`less effective therapy that would be available in a more timely fashion.
`The breaking of the ampule neck may result in exposing the patient to glass
`contamination of the product and exposing health care professionals to an increased
`risk of injuring themselves when handling and breaking the glass ampules.
`There is an increased probability of dosing errors by requiring health care
`professionals to dilute the product. Such errors may manifest themselves as an
`overdose or an underdose if the product is not diluted properly. Likewise, there is an
`additional possibility that the concentrated form will be administered "as is" which is
`contraindicated and can result in adverse events.
`
`-8-
`
`Sandoz Exhibit 1017 Page 8
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`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`The diluted form must be discarded in 24 hours due to stability issues.
`The selection of an inappropriate diluent can have an adverse effect on the stability
`and could cause breakdown of the drug.
`
`As stated in Dr. Brittain's Declaration, the development of a storage stable, ready-to-use
`nicardipinc hydrochloride intravenous product which the present invention provides addresses
`the issues presented above with respect to concentrated ampule formulations. In Dr. Brittain's
`opinion, the present invention has given the target patient population and the health care
`professionals serving them solutions for all of the needs described above.
`
`ii. There Was No Expectation Of Success ln Formulating A Stable Form Of A Low
`Concentration Drug
`
`Independent claim 40 recites a nicardipine hydrochloride range of about 0. 1 to about 0.4
`mglmL, and independent claims 44-46 recite a nicardipine hydrochloride range of about 0.1 to
`about 0.2 mglmL.
`
`As discussed in the Declaration by Dr. Drittain, a skilled formulator would not have
`expected the non-concentrated nicardipine hydrochloride composition defined by the present
`claims to be stable for long storage time periods in consideration of two separate and distinct
`issues:
`
`(i) The low concentration ofnicardipine hydrochloride results in a higher solvent(cid:173)
`to-drug ratio as compared to a concentrated nicardipine hydrochloride
`formulation. Since nicardipine hydrochloride is subject to hydrolysis and is
`known to degrade in the presence of water, one skilled in the art would have
`expected that the increased solvent-to-drug ratio in the ready-to-use low
`concentration formulation would cause increased degradation of the drug
`substance, especially if the formulation had been stored for an extended period of
`time. The phenomenon that lower concentrations of nicardipine hydrochloride
`are susceptible to increased degradation during storage is demonstrated in Figures
`4A and 4B of the present application. As shown in Figures 4A and 4B, the"%
`Total Impurities" is consistently higher for formulations ofO.l mglmL as
`compared to 0.2 mglmL.
`
`(ii) The low concentration of nicardipine hydrochloride results in a higher bag
`surface-to-drug ratio when compared to the surface-to-drug ratio of a concentrated
`formulation in a glass ampule. On the basis of this surface area consideration, one
`skilled in the art would have expected an increased degree ofnicardipine
`
`-9-
`
`Sandoz Exhibit 1017 Page 9
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`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`hydrochloride degradation during storage due to interaction of the nicardipine
`hydrochloride with the bag material. The phenomena that lower concentrations of
`nicardipine hydrochloride are susceptible to increased degradation as a result of
`bag interaction during storage is demonstrated in Figures SA and SB of the
`present application. As shown in Figure SA, the"% Drug Remaining" after 12
`weeks of storage in a polyvinyl chloride (PVC) container (Intravia®) resulted in a
`nicardipine hydrochloride net decrease of over 15%. PVC is the material
`described in the McFarlane reference for storage of the reconstituted nicardipine
`hydrochloride concentrate. In contrast, as shown in Figure 58 of U.S. Patent
`Application Serial No. 2007/0249689, when low concentration nicardipine
`hydrochloride is stored in a non-polar bag (e.g., Galaxy®) there is surprisingly
`minimal degradation even after 25 weeks storage.
`
`The degradation of drug is an especially important issue with the low concentration
`nicardipine hydrochloride compositions according to the present claims, as compared to the
`concentrated dosage forms of the prior art. This is due to the concern that the degradation of any
`amount of drug in a non-concentrated form will represent a greater percent of the overall drug
`content as compared to concentrated forms, and this aspect can severely limit the useful life for
`the low-dose formulation.
`
`The McFarlane reference does not describe a ready-to-use, low concentration nicardipine
`hydrochloride formulation as required by the present claims. Further, the McFarlane reference
`does not teach or suggest form1.,1lating and storing a ready-to-use nicardipine hydrochloride
`formulation such that the solution does not come into contact with polar polymers as recited in
`independent claim 40, or wherein the container is a copolyester, polyethylene, or polyoleftn as
`recited in dependent claim 43 and independent claims 44-46.
`
`The Kaiser reference is directed to health care waste and thus addresses a different
`problem (i.e., the incineration of plastic bags) than that which is solved by the present invention.
`The Kaiser reference provides no guidance on stability issues with a low concentration, solution(cid:173)
`phase, formulation of a drug substance that is subject to hydrolysis, such as nicardipine
`hydrochloride. As stated in the Declaration by Dr. Brittain, one skilled in the formulation arts
`would have no reason whatsoever to look to the Kaiser reference for guidance on fornmlating a
`stable low concentration, ready-to-use, nicardipine hydrochloride composition.
`
`-10-
`
`Sandoz Exhibit 1017 Page 10
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`

`

`Appl. No. 1 1/788,076
`Amendment dated July 6, 2009
`
`The only product described in the Kaiser reference as being stored in polyolefin
`containers is platelets. The Kaiser reference described that there was "no consistent differences"
`between PVC and polyolefin. As stated in the Declaration by Dr. Brittain, this observation
`provides further evidence that one of skill in the art would have had no expectation of success in
`
`preparing a stable, ready-to-use, low concentration formulation of the present invention. This
`unexpected success is evident in Figure 5B of the present application, which shows a "consistent
`difference" when comparing drug stability in polyolefin and PVC containers.
`
`Accordingly, Applicants respectfully request that the rejections of claims 40-41 and 43-
`44 under 35 U.S.C. § 103(a) over the McFarlane reference in view of the Kaiser reference be
`removed.
`
`iii. The Present Jnvention M.eets A .Long Felt Need .In The Art
`
`The claims of the present application encompass the following commercial products
`which have been approved by the United States Food and Drug Administration in 2008 as
`indicated in the FDA Orange Book (Approved Drug Products with Therapeutic Equivalence
`Evaluations) (See Exhibit D of Dr. Brittain's Declaration):
`
`nicardipine hydrochloride 20mg/200L (i.e., 0.1 mglmL) in 4.8% dextrose
`nicardipine hydrochloride 40mg/200L (i.e., 0.2 mglmL) in 5.0% dextrose
`nicardipine hydrochloride 20mg/200L (i.e., 0.1 mglmL) in 0.86% sodium chloride
`nicardipine hydrochloride 40mg/200L (i.e., 0.2 mglmL) in 0.83% sodium chloride
`
`The only injectable nicardipine hydrochloride products that had received FDA approval
`prior to the introduction of the above products were concentrated ampule products (2.5 mglmL)
`which were first approved in an NDA 16 years earlier (1992; see ExhibitD ofDr. Brittain's
`Declaration). In view of the issues previously discussed with respect to patients and health care
`personnel associated with concentrated ampule products, it is Dr. Brittain's opinion that a readyw
`to-use product would have been the first choice for commercialization in 1992 over a
`concentrated ampule product, and that there was an unmet market need for a ready-to-use non~
`concentrated product for the entire 16 year period until the approval of the previously described
`products in 2008. It is Dr. Brittain's further opinion that a non-concentrated ready-to-use
`
`-11-
`
`Sandoz Exhibit 1017 Page 11
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`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
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`product that solved the formulation issues associated with achieving a stable low concentration
`aqueous nicardipine formulation as discussed herein would have been successfully
`commercialized much sooner than 2008 and therefore, meets a long-felt need.
`
`Applicants respectfully submit that the Declaration of Dr. Brittain establishes that the
`present invention meets a long felt need in the art as (i) the need was persistent, (ii) the need was
`not met by another before the invention by applicant and (iii) the invention satisfies the long felt
`
`need (see MPEP 716.04 Section 1, 81h Edition, Incorporating Revision No.7).
`
`Applicants submit that a prima .facie case of obviousness has not been established in view
`of the McFarlane and Kaiser references. However, even assuming a prima facie case of
`obviousness has been established, Applicants respectfully submit that the secondary
`considerations of long felt need would rebut this finding.
`
`Accordingly, Applicants respectfully request that the rejections of claims 40-41 and 43-
`44 under 35 U.S.C. § 1 03(a) over the McFarlane reference in view of the Kaiser reference be
`removed for this reason as well.
`
`4. The McFarlane reference in view of the Kaiser reference and the Ogawa
`reference
`In the Office Action, claims 9, 11, 23, 30 and 42 were rejected under 35 U.S. C. § I 03(a)
`as being unpatentable over the McFarlane reference in view of the Kaiser reference and further
`in view of U.S. Patent No. 4,880,823 (the Ogawa reference). Applicants note that claims 9, 11,
`
`23 and 30 have been cancelled.
`
`In the Office Action, the Examiner has conceded that the combination of McFarlane and
`Kaiser does not teach the sorbitol levels as presently claimed and relies on Ogawa for describing
`preparations with sorbitol at the claimed levels.
`
`Applicants respectful traverse this rejection as the prior art teaches away from nicardipine
`hydrochloride compositions having the claimed amounts of sorbitol.
`
`-12-
`
`Sandoz Exhibit 1017 Page 12
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`

`

`Appl. No. 1 1/788,076
`Amendment dated July 6, 2009
`
`Claim 42 includes the limitation that the pharmaceutical composition comprises sorbitol
`
`at from about 1 mglmL to about 4 mglmL, and claims 45w46 include the limitation that the
`pharmaceutical composition comprises sorbitol at from 0 mg/mL to about 4 mg/mL.
`
`As discussed in the Declaration by Dr. Brittain, the Ogawa reference describes
`nicardipine formulations that must include a polyhydric alcohol (e.g., sorbitol) in an amount of
`
`2-7 w/v %. For example, at column 1, lines 46-51, the Ogawa reference states that:
`
`"As the result qffurther investigations, it has been discovered that when
`nicardipine chloride [sic] is dissolved in water together with 2 to 7 W!V% of a
`polyhydric alcohol, a stable aqueous solution ofnicardipine hydrochloride is
`unexpectedly obtained and based on the discovery. the invention has been
`attained"
`
`In the Ogawa reference, the unit of w/v% is a different measurement than the presently
`
`claimed measurement which uses units ofmglmL. However, as discussed by Dr. Brittain, it is
`well known in the art that the two units are related by the simple relation:
`
`w/v% is equivalent to (glmL) times 100
`
`Converting the poly hydric alcohol limitations of about I mg/mL to about 4 mg/mL in
`claim 42 according to this calculation yields a value of about 0.1 w/v% to about 0.4 w/v %,
`
`according to the following calculations:
`
`I mglmL = .001 glmL and .001 glmL * 100 = 0.1 w/v%
`4 mglmL = .004 glmL and .004 glmL * 100 = 0.4 w/v%
`
`As discussed above, the Ogawa reference teaches that in order to achieve stable aqueous
`solution of nicardipine hydrochloride, 2-7 w/v% is a necessary component. The lower limit of
`
`the range in the Ogawa reference (2 w/v %) is 500-2000% higher than the range in claim 42 (0.1
`w/v% to 0.4 w/v %). Similarly, claims 45 and 46 encompass stable aqueous nicardipine
`formulations that exclude sorbitol (0%) and that have an upper limit of 4 mg/mL (0.4 w/v %).
`Thus, the lower limit of the Ogawa reference (2 w/v %) is 500% higher than the upper limit of
`
`claims 45 and 46.
`
`wl3•
`
`Sandoz Exhibit 1017 Page 13
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`

`

`Appl. No. 111788,076
`Amendment dated July 6, 2009
`
`The Office Action points to Example 7 of the Ogawa reference which describes a 1
`mglmL nicardipine hydrochloride composition containing 20 mglmL sorbitol, which corresponds
`to a nicardipine-to-sorbitol ratio of 1 :20. The Examiner states that with a range of nicardipine of
`0.1 to 0.4 mglmL (as recited in claim 40) the ratio of 1 :20 would result in 2-8 mglmL sorbitol,
`which is within the claimed range. Thus, the Office Action states that if the nicardipine
`concentration is decreased in accordance with the present claims, the skilled artisan following the
`teaching of the Ogawa reference would linearly decrease the sorbitol to achieve the claimed
`range.
`
`This position by the Examiner goes against the direct teachings of Ogawa which require
`that the 2-7 w/v % concentration of sorbitol be maintained regardless of the concentration of
`nicardipine hydrochloride provided.
`
`As stated in the Declaration of Dr. Brittain, this is evidenced by Example 15 of Ogawa,
`which describes a 0.4 mglmL aqueous nicardipine hydrochloride formulaLion in an ampule
`(which is within the claimed range), but which includes 5 w/v% sorbitol (50 mglmL). This is
`further evidenced by the content of claim 1 of the Ogawa reference, which claims a composition
`of 0.04 w/v% (0.4 mglmL) nicardipine hydrochloride with a polyhydric alcohol content of 2-7
`w/v %. Thus, as discussed in the Declaration of Dr. Brittain, Ogawa teaches that 2-7 w/v% of
`sorbitol must be maintained, and that one skilled in the art following this clear teaching would
`not linearly decrease the sorbitol as the amount of nicardipine hydrochloride decreases as the
`rejection improperly suggests.
`
`As discussed in the Declaration of Dr. Brittain, the presently claimed formulations that
`feature decreased concentrations or even no sorbitol at all have unexpected stability in view of
`the contrary teachings of Ogawa. Example 7 of the Ogawa reference (which was referred to by
`the Examiner in the Office Action) had only 47.45% drug substance remaining undegraded after
`7 days of storage. The compositions of Examples 15-17 were stored for only 10 hours and
`therefore do not shed any light on the storage stability issue. Furthermore, even though the
`compositions of Examples 1-14 maintained undegraded drug substance in amounts greater than
`
`-14-
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`Sandoz Exhibit 1017 Page 14
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`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`90% after 4 weeks (see Examples 1-4) or 1 day (see Examples 7-14), these same compositions
`had at least a 25% decrease in drug content by the time of the last measurement at 12 weeks (see
`Examples l-4) and 7 days (see Examples 7-14). By contrast, compositions of the present
`invention have less than 10% decrease in the concentration of nicardipine hydrochloride and a
`total impurity formation ofless than about 3% after storage for three months, and even one year
`at room temperature.
`
`Accordingly, Applicants respectfully request that the rejection of claim 42 under 35
`U.S.C. § 103(a) over the McFarlane reference in view of the Kaiser reference and the Ogawa
`reference be removed.
`
`The Examiner is further directed to the discussion above regarding how the present
`invention meets a long felt need in the art as further evidence of the non-obviousness of the
`present invention over the McFarlane reference in view of the Kaiser reference and the Ogawa
`reference.
`
`C. Double Patenting Rejections
`In the Office Action, claims 1, 3-5 and 7-9 were provisionally rejected on the ground of
`nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 4, 7-8 and
`11-12 of co-pending U.S. Application No. 11/737,067.
`
`In response, Applicants note that claims l, 3-5 and 7-9 have been cancelled without
`prejudice.
`
`Accordingly, Applicants respectfu11y request that the double patenting rejection over co(cid:173)
`pending U.S. Application No. 11/737,067 be removed.
`
`-15-
`
`Sandoz Exhibit 1017 Page 15
`
`

`

`Appl. No. 11/788,076
`Amendment dated July 6, 2009
`
`HI. Conclusion
`It is believed that all claims are in condition for allowance. If the Examiner believes that
`issues may be resdlved by a telephone interview, the Examiner is invited to telephone the
`undersigned at (973) 597·2404. The undersigned may also be contacted by e·mail at
`
`rparadiso@lowenstein.com. All correspondence should be directed to the address listed below.
`
`AUTHORIZATION
`The Commissioner is hereby authorized to charge any fees that may be required, or credit
`any overpayment, to Deposit Account 50·1358.
`
`Respectfully submitted,
`Lowenstein Sandler .PC
`
`!Robert J. Paradiso I
`By: Robert J. Paradiso
`Attorney for Applicant
`Registration No. 41,240
`
`DOCKET ADMINISTRATOR
`LOWENSTEIN SANDLER PC
`65 Livingston Avenue
`Roseland, NJ 07068
`General Tel.: 973·597·2500
`
`-16-
`
`Sandoz Exhibit 1017 Page 16
`
`