ATTORNEY DOCKET NO.: 056291-5004—01
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`PATENT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re PATENT APPLICATION of:
`
`Confirmation No.
`
`2093
`
`EVANS et 31.
`
`Application No.:
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`10/872,784
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`Filed:
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`June 22, 2004
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`FOR:
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`FORMULATION
`
`vvvvvvvvvv
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`Group Art Unit:
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`1617
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`Examiner: Hui, San-ming R
`
`Date: August 21, 2008
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`AMENDMENT AND RESPONSE
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`This is in response to the Action mailed March 17, 2008, the time for responding to
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`which has been extended to and including September 17, 2008 by Petition and authorization for
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`payment of fees submitted herewith. Please amend the claims as presented below.
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`Table of Contents is presented on page 2 of this paper.
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`Table of References discussed is presented on page 3 of this paper.
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`Amendments to the Claims begin on page 4 of this paper.
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`Remarks/Arguments begin on page 6 of this paper.
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`Applicants wish to express their appreciation to the Examiner for taking the time for the
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`personal interview on July 15, 2008, with the undersigned, Dr. Gellert and two other
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`representatives of Applicants’ assignee, which interview will also be discussed further below.
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`The Examiner’s attention is called to the accompanying Declaration of Dr. Paul Richard
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`Gellert and Attachments thereto (hereinafter “the Gellert Declaration”), portions of which were
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`presented at the interview, and additional portions of which provide further factual and
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`documentary support for the patentability arguments presented during the interview.
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`It is believed that arguments presented in this response and the factual and documentary
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`support provided by the Gellert Declaration establish the patentability of the amended claims
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`presented below and should place this application in condition for allowance. Therefore early
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`and favorable consideration is respectfully requested. However, if any outstanding issues
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`nevertheless remain, it is respectfully requested that the Examiner telephone the undersigned to
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`expedite the resolution of such issues and the allowance of this application.
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`DBl/62070163. l
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`InnoPharma Exhibit 1096.0001
`
`

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`ATTORNEY DOCKET NO. : 056291-5004-01
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`Application No.: 10/872,784
`Page 2
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`For convenience of reference, the Remarks will be presented under the section headings
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`listed in the following Table of Contents, beginning on the page noted:
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`TABLE OF CONTENTS
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`
`
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`Section
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`Fag:
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`
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`TABLE OF CONTENTS .............................................................................................. ..
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`TABLE OF REFERENCES ......................................................................................... ..
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`CLAIM AMENDMENTS ............................................................................................. ..
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`REMARKS ................................................................................................................... ..
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`(1) Applicants’ Summary ofPersonal Interview July 15, 2008 .............................. ..
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`(2) Introduction and Background ............................................................................ ..
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`(3) Discussion of Claim Amendments ...................................................................... ..
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`(4) Claim Rejections - 35 USC § 103 ....................................................................... ..
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`(5) Applicants’ Response, Arguments and Declaration Supportfor the
`Patentability of the Presently Pending Claims .................................................. ..
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`(6) Corrections/Clarifications to Evans Application ................................................ ..
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`(7) Additional Tests and Data in Attachment C ...................................................... ..
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`(8) Fourth Information Disclosure Statement ......................................................... ..
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`(9) Conclusion ........................................................................................................... ..
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`2
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`3
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`4
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`6
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`6
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`8
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`10
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`l3
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`l4
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`26
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`27
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`29
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`31
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`DBl/62070163.1
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`InnoPharma Exhibit 1096.0002
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`

`

`ATTORNEY DOCKET NO. 2 056291-5004—01
`
`Application No.: 10/872,784
`Page 3
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`TABLE OF REFERENCES
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`Author/Inventor
`
`Reference Citation/Patent
`
`US Patent 4,212,863
`Cornelius (US ‘863)
`EP 0 346 014 A1 (corresponds to US Patent 5,183,814)
`
`Dukes (EP ‘014)
`
`
` Y.C. J. Wang and R. R. Kowal. Review of excipients and pH’s for
`Techno]. 54:152—169 (2000) Wang (1980)
`
` Dukes (US ‘8 14)
`
`Gupta (1999)
`
`Huber (US ‘520)
`
`Lopatin (1972)
`
`Mackey (1995)
`
`Nema (1997)
`
`
`
`
`
`US Patent 5,183,814 (corresponds to EP 0 346 013 A1)
`
`P.K. Gupta and GA. Brazeau (eds). Injectable Drug
`Development: Techniques to Reduce Pain and Irritation. Chapters 11 &
`17 Interpharm Press, Denver, Colorado (1999)
`
`
`US Patent 3,164,520
`
`P.V. Lopatin, V. P. Safonov, T. P. Litvinova and L. M. Yakimenko. Use
`of nonaqueous solvents to prepare injection solutions. Pharm. Chem. J.
`
`6:724-733 (1972)
`
`MA. Mackey, A.J. Conway and DJ. Handelsman. Tolerability of
`intramuscular injections of testosterone ester in oil vehicle. Hum.
`Reprod.10: 862-865 (1995)
`
`S. Nema, R.J. Washkuhn, and RI. Brendel. Excipients and their
`use in injectable products. PDA J. Pharm. Sci. Techno]. 51216671
`
`(1997)
`
`Physicians ’ Desk Reference (2 7th edition). 1277- l 278, 1350-13 54, 1391 -
`PDR (1973)
`1392 Medical Economics Company, Oradell, NJ (1973)
`
`Powell (1998)
`
`M. F. Powell, T. Nguyen, and L. Baloian. Compendium of excipients for
`parenteral formulations. PDA J. Pharm. Sci. Techno]. 521238—311 [pages
`238—255 provided] (1998)
`
`Riftkin (1964)
`
`Strickley 1 (1999)
`
`C. Riffkin, R. Huber and CH. Keysser. Castor oil as a vehicle for
`parenteral adminstation of steroid hormones. JPharm.Sci. 53: 891—5
`(1964)
`
`R. G. Strickley. Parenteral formulations of small molecule therapeutics
`marketed in the United States ( 1999) Part I. PDA J. Pharm. Sci. Techno].
`53:324~349 (1999)
`
`Strickley II (2000)
`
`R. G. Strickley. Parenteral formulations of small molecule therapeutics
`marketed in the United States ( 1999) - Part 11 PDA J. Pharm. Sci.
`Techno]. 54:69-96 (2000)
`
`Strickley HI (2000)
`
`R. G. Strickley. Parenteral formulations of small molecule therapeutics
`marketed in the United States (1999) - Part 111. PDA J. Pharm. Sci.
`
`parenteral products used in the United States. J. Parenteral Drug Assoc.
`34:452~462 (1980).
`
`DB 1162070163 .1
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`InnoPharma Exhibit 1096.0003
`
`

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`ATTORNEY DOCKET NO. : 056291—5004—01
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`Application No.: 10/872,784
`Page 4
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`IN THE CLAIMS:
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`This listing of claims will replace all prior versions and listing of claims in the application.
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`Listing of the claims:
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`Claims 1-34 (cancelled).
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`Claim 35 (new): A method of treating a hormonal dependent benign or malignant disease
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`of the breast or reproductive tract by administration to a human in need of such treatment an
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`intra—muscular injection of a pharmaceutical formulation comprising fulvestrant, a mixture of
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`from 10 to 30 % weight of a mixture of ethanol and benzyl alcohol per volume of formulation
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`and from 10 to 25 % weight of benzyl benzoate per volume of formulation and a sufficient
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`amount of a castor oil vehicle, whereby a therapeutically significant blood plasma fulvestrant
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`concentration of at least 2.5ngml'I is attained for at least 2 weeks after injection.
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`Claim 36 (new): A method of treating a hormonal dependent benign or malignant disease
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`of the breast or reproductive tract by administration to a human in need of such treatment an
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`intra—muscular injection of a pharmaceutical formulation comprising fulvestrant, a mixture of
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`from 10 to 30 % weight of a mixture of ethanol and benzyl alcohol per volume of formulation
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`and from 10 to 25 % weight of benzyl benzoate per volume of formulation and a sufficient
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`amount of a castor oil vehicle, whereby the formulation comprises at least 45mgml'l of
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`fulvestrant.
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`Claim 37 (new): The method as claimed in claim 35 or 36 wherein the formulation
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`comprises a mixture of from 15 to 25 % weight of a mixture of ethanol and benzyl alcohol per
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`volume of formulation and from 12 to 20 % weight of benzyl benzoate per volume of
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`formulation.
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`Claim 38 (new): The method as claimed in claim 35 or 36 wherein the formulation
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`comprises a mixture of from 8.5 to 11.5 % weight of ethanol per volume of formulation, from
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`8.5 to 11.5 0/0 weight of benzyl alcohol per volume of formulation and 12 to 18 "/5 weight of
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`DBl/62070163.l
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`InnoPharma Exhibit 1096.0004
`
`

`

`ATTORNEY DOCKET NO. : 056291—5004-01
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`Application No.: 10/872,784
`Page 5
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`benzyl benzoate per volume of formulation.
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`Claim 39 (new): The method as claimed in claim 35 wherein the blood plasma fulvestrant
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`concentration is attained for at least 3 weeks after injection.
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`Claim 40 (new): The method as claimed in claim 35 wherein the blood plasma fulvestrant
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`concentration is attained for at least 4 weeks after injection.
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`Claim 41 (new): The method as claimed in claim 35 wherein a therapeutically significant
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`blood plasma fulvestrant concentration of at least 3ng;ml'1 is attained for at least 2 weeks after
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`injection.
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`Claim 42 (new): The method as claimed in claim 35 wherein a therapeutically significant
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`blood plasma fulvestrant concentration of at least 8.5ngml‘l is attained for at least 2 weeks after
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`injection.
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`Claim 43 (new): The method as claimed in claim 35 wherein a therapeutically significant
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`blood plasma fulvestrant concentration of at least 8.5ngml‘1 is attained for at least 4 weeks after
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`injection.
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`Claim 44 (new): The method as claimed in claim 35 or 36 wherein the total volume of
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`the formulation administered to said human is 6ml or less, and the concentration of fulvestrant in
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`said formulation is at least 45mgml'l.
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`Claim 45 (new): The method as claimed in claim 35 or 36 wherein the total volume of
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`the formulation administered to said human is 6ml or less, and the total amount of fulvestrant in
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`said volume of formulation is 250mg or more.
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`Claim 46 (new): The method as claimed in claim 35 or 36 wherein the benign or
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`malignant disease is breast cancer.
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`DB 1/62070163. l
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`InnoPharma Exhibit 1096.0005
`
`

`

`ATTORNEY DOCKET NO. : 056291-5004-01
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`Application No.: 10/872,784
`Page 6
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`REMARKS
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`This Amendment and Response is being filed as a follow-up to the personal interview
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`with Examiner Hui on July 15, 2008, in order to formally present the amended claims and the
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`patentability arguments that were discussed at the interview, and to formally present and
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`supplement by means of the accompanying Gellert Declaration the factual and documentary
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`support for the arguments presented at the interview.
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`(1) Applicants’ Summary ofPersonal Interview July 15, 2008
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`Applicants wish to thank the Examiner for extending a personal interview in this
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`Application on July 15, 2008 to the undersigned and three representatives of Applicants’
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`assignee, AstraZeneca AB.
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`Attending this interview on behalf of Applicants, in addition to the undersigned US
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`attorney, were Dr. Paul Gellert, the declarant on the attached Gellert Declaration and a Senior
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`Principal Scientist for AstraZeneca; Dr. Allen Giles, a European Patent Attorney with
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`AstraZeneca; and Dr. Balvinder Matharu, a patent trainee for AstraZeneca, all working out of the
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`AstraZeneca facilities at Mereside, Alderley Park, Macclesfiled, England.
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`In order to facilitate the discussion during the interview, the undersigned faxed to
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`Examiner Hui on July 14, 2008, a partial draft of the Gellert Declaration (having the substantive
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`content of paragraphs 1-9 of the attached Gellert Declaration and Attachments A, B and C), and
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`a partial draft of this Amendment and Response, including the amended claims and the substance
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`of the “Introduction and Background” and “Claim Amendment” portions of the present
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`Amendment and Response (Sections (2) and (3) of the Remarks).
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`During the course of the interview the Examiner was also given a copy of a corrected
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`version of Table 1 from the present application with an attached explanation of the corrections
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`(see Attachment D to the Gellert Declaration); a two page document showing the structure and
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`solubility of certain steroids in castor oil and sesame oil compared to the structure and solubility
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`of fulvestrant, and the solubility of certain steroids in benzyl benzoate (see Attachment E to the
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`Gellert Declaration); and a copy of Huber (US ‘520) referred to in Attachment E, which is
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`included as Tab 5 of the Compendium of Attachment F to the Gellert Declaration.
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`All of the above-noted drafts and documents that were provided to Examiner Hui were
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`DB 1/62070163 .1
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`InnoPharma Exhibit 10960006
`
`

`

`ATTORNEY DOCKET NO. : 056291—5004-01
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`Application No.: 10/872,784
`Page 7
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`discussed during the interview, as were the subject application (as published), the present Action
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`and, generally, the applied references.
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`The undersigned briefly commented on the prior art cited in the obviousness rejection as
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`disclosing, separately or in various sub-combinations, each of the fulvestrant, castor oil, ethanol,
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`benzyl alcohol and benzyl benzoate components of the formulation administered in the claimed
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`method. Then the undersigned and Dr. Gellert went through a summary of Applicants’ argument
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`as outlined in the Introduction and Background portion of partial draft response and the
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`additional data presented with the draft portion of the Gellert Declaration that had been sent to
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`the Examiner prior to the interview.
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`In brief summary it was argued (and it is believed was demonstrated) that the skilled
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`formulator tasked with developing an intramuscular (IM) inj ectable formulation for the sustained
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`release of fulvestrant, would have conducted a literature review for previously approved and/or
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`commercially marketed injectable formulations to identify potential solvents and cosolvents
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`meriting further consideration. A preformulation solubility screen would then have been
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`conducted to determine the solubility of fulvestrant separately in a range of pure solvents,
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`including potential solvents and cosolvents identified in the literature review. Based on the
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`results of these preformulation investigations, the experienced formulator would have selected a
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`castor oil based vehicle, but would have been led away from adding benzyl benzoate as a
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`cosolvent for fulvestrant when attempting to increase the fulvestrant concentration in the castor
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`oil vehicle up to the target level. Many commercialized steroids were more soluble in benzyl
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`benzoate than in the oil base of the vehicle as disclosed in Riffkin (1965), I and benzyl benzoate
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`could thus act as a cosolvent. However, fulvestrant is even less soluble in benzyl benzoate than it
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`is in castor oil and therefore its addition to castor oil would have been expected (and has been
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`shown) to further decrease the ability of the resulting castor oil-based vehicle to dissolve
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`fulvestrant.
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`It was therefore unexpected and surprising when Applicants found that the addition of
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`benzyl benzoate to a castor oil/alcohol mixture would increase the solubility of fulvestrant in the
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`formulation as presently claimed, permitting the target fulvestrant concentration to be attained
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`1 See Table of References at page 3 above; a copy of each reference is included in Attachment F to the Gellert
`Declaration under the Tab number indicated in the Table of References.
`
`DBli’62070163J
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`InnoPharma Exhibit 10960007
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`

`

`ATTORNEY DOCKET NO. : 056291-5004-01
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`Application No.: 10/872,784
`Page 8
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`with a more desirable lower level of alcohol cosolvent. It was pointed out at the interview that
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`this unexpected positive effect of benzyl benzoate on the solubility of fulvestrant in the castor
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`oil/alcohol mixture is shown by the data in Table 3 of the Evans specification. Moreover, the
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`data from the additional testing overseen by Dr. Gellert and presented in Attachment C to his
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`Declaration demonstrates that this unexpected positive benzyl benzoate effect is present across
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`the broader range of formulation composition as presently claimed.
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`Dr. Gellert additionally commented at the interview on certain transcription and other
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`errors in Tables 3 and l of the Evans Application relative to the underlying laboratory notebook
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`data and other source materials, and provided clarification by means of handwritten notations on
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`copies of these Tables, which are Attachments A and D to his Declaration.
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`At the conclusion of the interview Examiner Hui indicated that the allowability of the
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`amended claims would be viewed favorably in light of the factual presentation of the draft
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`Gellert Declaration and the arguments presented at the interview. The recitations and
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`Attachments to the draft Gellert Declaration discussed at the interview have been retained in the
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`executed Gellert Declaration submitted herewith. The executed Gellert Declaration also includes
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`additional support for the unobviousness of the presently claimed invention, backed up by
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`literature and patent documents in the Compendium and discussion further below.
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`(2) Introduction and Background
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`The invention as presently claimed and disclosed in the subject application is broadly
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`directed toward a method of treating a hormonal dependent benign or malignant disease of the
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`breast or reproductive tract in a human by administration of an intramuscular injection of a
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`sustained release pharmaceutical formulation comprising fulvestrant.
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`Even relative to other difficult to formulate steroidal based compounds, fulvestrant is a
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`particularly lipophilic molecule having extremely low aqueous solubility. The invention
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`therefore addresses the objective of defining (a) a pharmaceutically acceptable solvent or mixture
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`of solvents (b) that will dissolve a sufficient quantity of fulvestrant [at least 250 mg] (c) to form a
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`small enough volume of formulation that is acceptable for injection [6 ml or less] and will
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`provide ((1) a fulvestrant concentration of at least 45mgml'I [claim 36] and/or (e) the sustained
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`DB 1562070163.!
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`InnoPharma Exhibit 1096.0008
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`

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`ATTORNEY DOCKET NO. : 056291—5004-01
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`Application No.: 10/872,784
`Page 9
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`release of fulvestrant whereby a therapeutically significant blood plasma fulvestrant
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`concentration of at least 2.5ngml'1 is attained for at least 2 weeks [claim 35].
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`The person of ordinary skill in the art involved in developing formulations for the
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`parenteral administration of new, difficultly soluble compounds such as fulvestrant would be a
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`person having specialized training and experience in developing pharmaceutical formulations
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`and methods for their administration. Such person would be aware of commercialized sustained
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`release injectable steroidal formulations, such as those included in Table l of the Evans
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`specification, which commonly use oil to solubilize the compound and may have various
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`additional excipients. The Evans specification acknowledges, as relevant here, that such known
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`formulations include oils such as castor oil and may include one or more other excipients such as
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`benzyl alcohol, ethanol and benzyl benzoate. However, such person would begin the
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`development of a suitable formulation for fulvestrant by determining the solubility of fulvestrant
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`in various single solvents that have previously been used in injectable formulations.
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`A selection of such solubility data for fulvestrant is listed in Table 2 of the Evans
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`specification, from which it can be seen that fulvestrant is significantly more soluble in castor oil
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`than any of the other oils tested. However, as noted in paragraph [0017] of the Evans
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`specification, 2 the solubility of fulvestrant in castor oil alone would not meet the above criteria.
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`Table 2 shows a very high solubility of fulvestrant in benzyl alcohol and ethanol, and adding an
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`alcohol component to the castor oil would be seen as a clear choice to the skilled person. Dukes
`(US ‘814) took this approach in his Example 3, where his formulation contained 50 mg of
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`fulvestrant, 400 mg of benzyl alcohol and sufficient castor oil to bring the solution to a volume
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`of 1 ml, or about 40% w/v benzyl alcohol. While this may have provided acceptable solubility of
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`fulvestrant in an experimental quantity of formulation to demonstrate selective oestrogen therapy
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`in rats, the Evans specification in paragraph [0015] notes that this very high alcohol
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`concentration would complicate manufacture on a commercial scale, and that there is a need to
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`lower the alcohol concentration whilst preventing precipitation of fulvestrant from the
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`formulation. Moreover, the skilled person would want to reduce the level of alcohol cosolvents
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`to minimize their potential to adversely impact performance including tolerability.
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`2 Reference made herein and in the Gellert Declaration to paragraphs of the Evans specification refer to the
`numbered paragraphs of the published application, US 200550043285 A1, published February 24, 2005.
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`DBlf62070163J
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`InnoPharma Exhibit 10960009
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`

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`ATTORNEY DOCKET NO. : 056291—5004—01
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`Application No.: 10/872,784
`Page 10
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`The focus of the present invention, therefore, resulted from the discovery by Applicants
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`of the unexpected positive effect of benzyl benzoate in significantly increasing the solubility of
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`fulvestrant when added to a castor oil/‘alcohol mixture, whereby the needed therapeutic amount
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`of fulvestrant could be dissolved in a small enough volume of formulation for injection without
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`need for an excessive amount of alcohol. This was truly surprising since the solubility of
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`fulvestrant in benzyl benzoate is significantly lower than the solubility of fulvestrant either in the
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`alcohol component or in castor oil. See Table 2 and specification paragraphs [0019] and [0051]
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`of the Evans Application. This positive effect of benzyl benzoate in significantly increasing
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`fulvestrant solubility in the castor oil/alcohol mixture is demonstrated by the data in Table 3 of
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`the specification, and is confirmed and amplified by the further evidence presented in the Gellert
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`Declaration and tabulated in Attachment C thereto.
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`The Examiner will note that the claims presented above cover a broader range of total
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`alcohol and benzyl benzoate content than the rejected previously pending claims. However, it
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`will be apparent from the above summary and the following discussion that the inventive step
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`(non-obviousness) of the present invention does not reside in any particular range of solvent
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`concentration, but lies in Applicants’ counter-intuitive addition of benzyl benzoate to the
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`fulvestrant formulation, and the unexpected positive effect of this benzyl benzoate addition on
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`increasing fulvestrant solubility. The further data provided by the Gellert Declaration confirms
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`that the addition of benzyl benzoate unexpectedly significantly increases the solubility of
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`fulvestrant over the broader range of formulation composition as presently claimed.
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`(3) Discussion of Claim Amendments
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`Claims 24—34 are newly cancelled above (claims 1-23 having been previously cancelled)
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`and replaced by new claims 35-46. The cancellation of these claims is without disclaimer or
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`prejudice to Applicant’s right to prosecute any subject matter that may have been deleted thereby
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`in one or more continuing applications.
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`As with cancelled claims 24-34, new claims 35—46 are directed toward a method of
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`treating a hormonal dependent benign or malignant disease of the breast or reproductive tract by
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`administration to a human in need of such treatment an intra—muscular injection of a
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`DBli’62070 1 63.1
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`InnoPharma Exhibit 1096.0010
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`

`

`ATTORNEY DOCKET NO. : 056291—5004—01
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`Application No.: 10/872,784
`Page 11
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`pharmaceutical formulation as recited in the various claims. As in cancelled claim 24, the
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`method of new independent claim 35 provides that “a therapeutically significant blood plasma
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`fulvestrant concentration of at least 2.5ngml'l is attained for at least 2 weeks after injection.” As
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`in cancelled claim 29, the method of new independent claim 36 provides a formulation that
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`“comprises at least 45mgml’1 of fulvestrant.” As in cancelled claims 26 and 31, new dependent
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`claim 46 is specifically directed toward the method wherein the hormonal dependent benign or
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`malignant disease is breast cancer.
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`The particular ranges of formulation composition or other characteristics recited in new
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`claims 35-46 find support in the specification as follows:
`
`0
`
`Support for the recitation in new independent claims 35 and 36 of “from 10 to 30 %
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`weight of a mixture of ethanol and benzyl alcohol per volume of formulation and from 10
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`to 25 % weight of benzyl benzoate per volume of formulation” is found in the published
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`specification, inter alia, at line 13 of paragraph [0031] and at line 16 of paragraph [0036].
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`0
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`Support for the recitation in new dependent claim 37 of “from 15 to 25 % weight of a
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`mixture of ethanol and benzyl alcohol per volume of formulation and from 12 to 20 %
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`weight of benzyl benzoate per volume of formulation” is found in the published
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`specification, inter alia, at line 13 of paragraph [0031] and at line 17 of paragraph [0036].
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`0 As with cancelled claims 24 and 29, support for the recitation in new dependent claim 38
`
`of “from 8.5 to 11.5 % weight of ethanol per volume of formulation” and “from 8.5 to
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`11.5 % weight of benzyl alcohol per volume of formulation” is found in the published
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`specification, inter alia, at lines 9—14 of paragraph [0031] wherein one of the preferred
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`ranges of pharmaceutically-acceptable alcohol (total) is “17-23%w/v” at line 14. The
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`immediately following paragraph [0032], lines 3-7, discloses that the pharmaceutically—
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`acceptable alcohol is “preferably a mixture of two alcohols,” specifically noting a
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`mixture of ethanol and benzyl alcohol, and that “preferably the ethanol and benzyl
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`alcohol are present in the formulation in the same w/v amounts.” Support for the
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`recitation of “12 to 18 0/o weight of benzyl benzoate per volume of formulation” is found,
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`inter alia, at line 17 of paragraph [0036].
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`0
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`Support for the recitation in new dependent claim 39 of “wherein the blood plasma
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`DB1/62070163. 1
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`InnoPharma Exhibit 1096.0011
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`

`

`ATTORNEY DOCKET NO. : 056291-5004-01
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`Application No.: 10/872,784
`Page 12
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`fulvestrant concentration is attained for at least 3 weeks after injection” is found in the
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`published specification, inter alia, at lines 1-2 of paragraph [0048].
`
`0
`
`Support for the recitation in new dependent claim 40 of “wherein the blood plasma
`
`fulvestrant concentration is attained for at least 4 weeks after injection” is found in the
`
`published specification, inter alia, at lines 2-3 of paragraph [0048].
`
`0
`
`Support for the recitation in new dependent claim 41 of “wherein a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 3ngml'1 is attained” is found
`
`in the published specification, inter alia, at line 3 of paragraph [0047].
`
`0
`
`Support for the recitation in new dependent claim 42 of “wherein a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 8.5ngml'l is attained” is
`
`found in the published specification, inter alia, at line 3 of paragraph [0047].
`
`0
`
`Support for the recitation in new dependent claim 43 of “wherein a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 8.5ngml‘l is attained for at
`
`least 4 weeks after injection” is found in the published specification, inter alia, at line 3
`
`of paragraph [0047] and at lines 2-3 of paragraph [0048].
`
`0
`
`Support for the recitation in new dependent claim 44 of “wherein the total volume of the
`
`formulation administered to said human is 6ml or less, and the concentration of
`
`fulvestrant in said formulation is at least 45mgml'1” is found in the published
`
`specification in paragraph [0027].
`
`0
`
`Support for the recitation in new dependent claim 45 of “wherein the total volume of the
`
`formulation administered to said human is 6ml or less, and the total amount of fulvestrant
`
`in said volume of formulation is 250mg or more” is found in the published specification
`
`in paragraph [0028].
`
`0
`
`Support for the recitation in new dependent claim 46 of “wherein the benign or malignant
`
`disease is breast cancer” is found in the published specification, inter alia, at lines 1-7 of
`
`paragraph [0058] and in paragraph [0062].
`
`It should be clear from the above paragraphs, all limitations of new claims 35-46 find
`
`support in the specification, and these new claims are believed to be in proper form in all
`
`respects. Accordingly, entry of these amendments is believed to be in order and is respectfully
`
`DEM/620701631
`
`InnoPharma Exhibit 1096.0012
`
`

`

`ATTORNEY DOCKET NO. : 0562915004-01
`
`Application No: 10/872,784
`Page 13
`
`requested. Following entry of these amendments, claims 35—46 remain pending in this
`
`application.
`
`(4) Claim Rejections - 35 USC § 103
`
`Claims 24-34 have been rejected under 35 USC § 103 (a) as being unpatentable over
`
`Dukes, EP 0 346 014 (hereinafter “Dukes (EP ‘014)”)3 in View of Lehmann et a], US Patent Re
`
`28,690 (hereinafter “Lehmann”), GB 1 569 286 (hereinafter “GB ‘286), Osborne et al., Journal
`
`of National Cancer Institute, 1995;87(10):746-750 (hereinafter “Osborne”), and Remington’s
`
`Pharmaceutical Sciences (hereinafter “Remington”). The Examiner applies these references to
`
`the rejection as follows:
`
`0 Dukes is said to teach that antiestrogen agents, including fulvestrant, are useful in treating
`
`postmenopausal symptoms such as urogenital atrophy affecting the vagina (citing page 3,
`
`lines 56-page 4, line 1; also page 7, line 28—29). Dukes is said to further teach that
`
`antiestrogen agents, including fulvestrant, may be used in a dosage of 50mg to 5 g in
`
`vehicle comprising castor oil and benzyl alcohol (citing page 7, 20-24).
`
`0 Lehmann er a1. is said to teach that benzyl benzoate and castor oil are well—known solvent
`
`useful as conventional carriers for steroids (citing col. 1, line 21-26).
`
`0 GB ‘286 (also by Lehmann) is said to teach an intramuscular injection of testosterone
`
`derivative containing castor oil/benzoate in the ratio of 6:4 (citing page 1, line 17).
`
`o Osborne et al. is said to teach fulvestrant as useful in treating human breast cancer (citing
`
`pages 747—748).
`
`0 Remington is said to teach that ethanol is one of the most commonly used solvents in
`
`pharmaceutical industry (citing page 219).
`
`The Examiner concluded at page 4 of the Action that combining one or more agents,
`
`which are known to be useful as commonly used solvents, such as benzyl benzoate, ethanol,
`
`castor oil, and benzyl alcohol, together and incorporating such combination with an estrogen
`
`derivative, fulvestrant, would be reasonably expected to be useful in formulating a
`
`3 This Dukes reference (Dukes (EP ‘014)) is the European counterpart of US 5,1818 14 (Dukes (US ‘814)) noted in
`paragraph [0014] of the published specification.
`
`DBl/62070163.1
`
`InnoPharma Exhibit 10960013
`
`

`

`ATTORNEY DOCKET NO. : 056291—5004—01
`
`Application No: 10/872,784
`Page 14
`
`pharmaceutical composition; and that employing such fulvestrant-containing composition to treat
`
`urogenital atrophy would be reasonably expected to be effective.
`
`The Examiner further concluded that the optimization of parameters such as the amount
`
`of excipients, dosage range, and dosing regimens, is “obvious as being within the skill of the
`
`artisan, absent evidence to the contrary,” and that maintaining the plasma concentration of the
`
`active compound as claimed would be considered “obvious as being within the purview of the
`
`skilled artisan, absent evidence to the contrary.”
`
`Applicants respectfully traverse this obviousness ground for rejection based on the
`
`following arguments and the support therefore provided by the Gellert Declaration.
`
`(5) Applicants’ Response, Arguments and Declaration Support
`for the Patentabililjy ofthe Presently Pending Claims
`
`The invention as disclosed and presently claimed in the subject application is broadly
`
`directed toward a method of treating a hormonal dependent benign or malignant disease of the
`
`breast or reproductive tract in a human by administration of an intramuscular (1M) injection of a
`
`sustained release pharmaceutical formulation comprising fulvestrant. Fulvestrant is the non-
`
`proprietary name for the subsequently approved and commercialized drug now known as
`
`Faslodex®.
`
`The invention is focused in particular on the discovery of a novel and unobvious
`
`formulation for this extremely difficult to formulate molecule, which formulation is suitable for
`
`intramuscular injection to a human patient and is capable of dissolving the therapeutic target
`
`amount of fulvestrant in a small enough volume for IM administration, and which formulation
`
`provides for the satisfactory sustained release of fulvestrant over an extended period of time as
`
`specified in the present claims.
`
`Oestrogen deprivation is fundamental to the treatment of many benign