Docket No.: 63877200030 1
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Appl ication of:
`Neil P. DESA I et al.
`
`A pplication No.: 11/553.339
`
`Confilmation No.: 3605
`
`Filed: October 26 , 2006
`
`Foe COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`AGENTS
`
`Art Unit: 1656
`
`Examiner: M. Tsay
`
`AM ENDMENT IN RESPONSE TO NON-FINAL OFFICE ACTION
`
`M S Amendment
`Commissioner for Patents
`P.O. Box 1450
`AlexandJia, VA 22313-1 450
`
`Dear Si r:
`
`INTRODUCTORY COMMENTS
`
`This is in response to the non-fina l Office Action dated April 28, 2009 (Paper No.
`
`20090415), for which a response was du e on July 28, 2009. Filed herewith is a Petition and fee for
`
`a Ihree month(s) extension of time, thereby extending the dead line for re sponse to October 28, 2(}09.
`
`Accordingly, this response is time ly fi led. Reconsideration and al lowance of the pending claims, as
`
`amended, in light of the remarks presented herein are respectfully requested.
`
`Amendments to the Claims are reflected in the listi ng of c1.nim s which begins on page 2
`
`of this paper.
`
`Remarks/Arguments begin on page 5 of this paper.
`
`pa -1336926
`
`Apotex v. Abraxis - IPR20 18-0015 3, Ex. 1020, p.OI of 10
`
`

`

`Application No.: 111553,339
`
`2
`
`Docket No.: 638772000301
`
`AMENDMENTS TO THE CLAIMS
`
`This listing of claims will replace all prior versions, and Listings, of
`
`claims in the application:
`
`Claim I (Cancelled)
`
`Clai m 2 (CutTently amended): A phannaceurical composition comprising a phannaceutical agent
`
`and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carTier
`
`comprises al bumin, wherei n the albumin and the pharmaceutical agent in the composition are
`
`fOlmulated as nanoparticles, and wherein the weight ratio of albumin to pharmaceutical agent in the
`
`composition is about 1: Ito about -*1-9: 1.
`
`Claim 3 (Previou sly presented): T he pharmaceutical composition of claim 2, wherein the
`
`nanoparticles have a mean-diameter of less than about 200 nm.
`
`Claim 4 (Previously presented): The phannaceutical composition of cla im 2, wherein the al bumin
`
`is human serum albumin.
`
`Claim 5 (Previously presented): The phannaceutical composition of claim 2, wherein the
`
`phmmaceuti cal agent is selected from the group consisting of anticancer agents, anesthetics,
`
`anti microtubule agents, agents to treat cardiovascular disorders, ant ihypertensives, anti (cid:173)
`
`inflammatory agent s, anti-al1hritic agents, anliaslhmatics, analgesics, vasoactive agents,
`
`immunosuppressi ve agents, antifungal agents, antiarrhythmic agents, antibiotics, and hOlmones.
`
`Claim 6 (Previous ly presented): The pharmaceutical composition of claim 5, wherein the
`phannaceutical agent is an anticancer agent.
`
`Claim 7 (Wi thdrawn): The pharmaceutical composition of claim 5, wherein the pharmaceutical
`agent is an anti-inflammatory agent.
`
`Claim 8 (Withdrawn): The pharmaceutical composition of claim 5, wherein the phannacelltical
`agent is an immunosuppressive agent.
`
`pa -1336926
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1020, p.02 of 10
`
`

`

`Application No.: 111553,339
`
`3
`
`Docket No.: 638772000301
`
`C laim 9 (Withdrawn): The phaJrnaceutical composition of claim 5, wherein the pharmaceutical
`agent is an antibiotic.
`
`Claim 10 (Previously presented): The pharmaceutical composition of claim 2, wherein the
`
`pharmaceutical agent is selected from the group consisting of paclitaxel, docetaxel, taxanes,
`
`camptothecin, propofol, amiodarone, cyclosporine, rapamycin, amphoterici n, liothyronine,
`
`epoth ilones, colchicines, thyroid hormones, vasoactive intestinal peptide, corticosteroids,
`
`melatonin, tacrolimus, mycophenolic ac ids.
`
`C laim II (Previously presented): The pharmaceutical composition of claim 10, wherein the
`anticancer agent is a taxane.
`
`Claim 12 (previously presented): The pharmaceutical composition of claim II, wherein the
`pharmaceutical)lgent is paclitaxel.
`
`C laim 13 (Previously presented): The pharmaceutical composition of claim 12. wherein the
`pharmaceutical composition is free of Cremophor.
`
`Claim 14 (Withdrawn): A method of treating a di sease comprising admi ni stering an effective
`
`amount of a pharmaceutical composit ion of claim 2.
`
`Claim 15 (Withdrawn): The method of claim 14, wherein the disease is cancer.
`
`Claim 16 (Wi thdrawn): The method of claim 14. wherein the disease is 3.l1hritis.
`
`Claim 17 (Withdrawn): The method of claim 14, wherein the d isease is cardiovascular disease.
`
`Claim 18 (Withdrawn): The method of claim 17, wherein the di sease is restenosis.
`
`Claim 19 (Wi thdrawn): The method of claim 14, wherein the composition is administered
`
`intravenously, intraarterially, intrapulmonary, orally, by inhalation , intravasicularly,
`
`intramuscularly, intra-tracheally, subcutaneously, intraocularly, intrathecally, or tran sdermally.
`
`pa-1336926
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1020, p.03 of 10
`
`

`

`Application No.: 111553,339
`
`4
`
`Docket No.: 638772000301
`
`C laim 20 (W ithdrawn): The method of claim 19, wherein the pharmaceutical composition is
`
`admin istered intravenously.
`
`Claim 2 J (Wi thdrawn): The method of claim J 9, wherei n the phannaceutical composi tion is
`
`administered orally.
`
`Claim 22 (Wi thdrawn and Currentl y Amended) : A method of prepari ng a phannaceutical
`
`composition of claim 2, com prising combin ing a pharmaceutical agent with a pharmaceuti call y
`
`acceptable carrier comprising alb umin, wherein the weight ratio or albumin to the pharmaceuti cal
`
`agent in the composi tion is aBeli1 5: I er Ie!>!> about I: I to about 9: I.
`
`Cl aim 23 (Withdrawn): The method of claim 22, fUl1her compri sing su bjecting the combination of
`
`the phannaceuticul agent and the phunlluceutically acceptable canier to high pre!'i!'iure
`
`homogenization.
`
`C laim 24 (New): The phmmaceutical compos ition of claim 2, wherein the ratio (w/w) of albumin to
`
`the phannaceutical agent in the phaJ11laceuticai co mposition is about 1: I to about 5: I.
`
`C lai m 25 (New): The phalmaceutical compos ition of clai m 2, wherein the ratio (w/w) of albumi n to
`
`the phmmaceutical agent in the phm11laceu tical composition is 1: I to 9: I.
`
`pa -1336926
`
`Apotex v. Abraxis - IPR201 8-00153 , Ex. 1020, p.04 of 10
`
`

`

`Application No.: 111553,339
`
`5
`
`Docket No.: 638772000301
`
`REMARKS
`
`Claims 2-23 are pending in the present application. Claims 7-9 and 14-23 are withdrawn
`
`from consideration. By this amendment, pending claims 2 and withdrawn claim 22 are amended.
`
`New claims 24 and 25 are added. Upon entry of this amendment, clai ms 2-6, 10- 13, and 24~25 are
`
`under examination.
`
`Support for the amendment of claim 2 and 22 can be found at page 14, line 21 (Paragraph
`
`[0041]) of the specification .
`
`With respect to claim ame ndments and canceiJation, Applicants ha\'e not dedicated or
`
`abandoned any unclaimed subject matter and moreover have not acquiesced to any rejections and/or
`
`objections made by the Patent Office. Applicants expressly reserve the right to pursue prosecution
`
`of any presently excluded subject matter or claim embodiments in one or more future continuation
`
`and/or divisional application(s).
`
`Summary oJillterview
`
`Applicants express their gratitude for the telephonic interview between Examiner Marsha M.
`
`Tsay and App licants' representative Jian (Janet) Xiao on May 19,2009. The time and cons ideration
`
`of the Examiner is greatly appreciated.
`
`During the May 19, 2009 interview, the Examiner and Applicants' represen tati ves brien y
`
`d iscussed the 35 U.S.C. § 103(a) rejection c ited in the Office Action. Applicants inquired about the
`
`possibility of amending the independent claim to recite a ratio of "about I: I to about 9: I. " The
`
`Examiner indicated that such amended claim will be examined.
`
`Rejection under 35 US.c. § I03(a)
`
`Claims 2-6 and 10-13 are rejected under 35 U.S.c. § 103(a) as allegedly being unpatentable
`
`over Damascelli e t al. ("Damascelli ," 2001 Cancer 92( 10): 2592-2602) in view of Ibrahim et al.
`
`(" Ibrahim," 2000 Proc Am Soc Clin Onco 19: abstract 609f). Applicants respectfully traverse thi s
`
`rejection. The response addresses claims as amended, and the arguments presented herein apply
`
`equally to the claims prior to the amendment.
`
`pa -1336926
`
`Apotex v. Abraxis - IPR2018-00IS3 , Ex. 1020, p.OS of 10
`
`

`

`Application No.: 111553,339
`
`6
`
`Docket No.: 638772000301
`
`The claims as amended are directed to "a pharmaceutical composition comprising a
`
`pharmaceutical agent and a pharmaceutically acceptable carrier, wherein the phalmaceutically
`
`acceptable carrier complises albumin, wherein the albumin and the pharmaceutical agent in the
`
`composition are formulated as nanopartic les, and wherein the weight ratio of albumin to
`
`pharmaceutical agent in the composition is about I: I to about 9: I. " The present application teaches
`
`th at a low albumin/pharmaceutical agent ratio, such as the ratios recited in the claims of the present
`
`application, allows enhanced cellu lar binding and transpol1 of the pharmaceutical agent. As stated
`
`in paragraph [0041] of the present application,
`
`Not to adhere to anyone particu lar theory, it is believed that the ratio of protein, e.g., human
`serum albumin, to phannaceutical agent in the pharmaceutical composition affects the
`ability of the phalmaceu ti cal agent to bind and transpOl1 the pharmaceutical agent to a cell.
`In this regard, higher ratios of protein to phannaceutical agent generally are associated with
`poor cell binding and tran spOl1 of the pharmaceulical agent, which possibly is the re~;u Jt of
`competition for receptors at the cell sUlf ace. The ratio of protein, e.g., albumin, to active
`pharmaceutical agent must be such that a sufficient amount of pharmaceutical agent bi nds
`to, or is transpol1ed by, th e cell.
`
`Example 45 demonstrates that increasing amounts of albumin can compete with the binding
`
`of a pharmaceutical agent, namely, paclitaxel, to the ceU slilface, and states that " higher albumin
`
`concentration inhibited binding of paclitaxel. Thus, invention compositions having lower amounts
`
`of albumin are preferred."
`
`The present application further teaches that a low albumin/pharmaceutical agent ratio, such
`
`as the ratios recited in cla ims of the present appl ication, allows formation of stable nanoparticle
`
`compositions of the pharmaceutical agent. Specificall y, Example 46 states,
`
`To in vestigate if lower amounts of albumin in the composition would affect stability of the
`inventi ve pharmaceutical composition, albumin-paditaxel composi tions with low amounts
`of albumin were prepared. It was found that these compositions were as stable a s
`compositions with higher quantities of albumin when examined for several months at
`different temperatures (2-8 "C, 25 °C, and 40°C) for potency of pacl itaxel, impurity
`formation, particle size, pH and other typical parameters of stability. Thus compositions
`with lower amounts of albumin are preferred as this can greatly reduce cost as well as allow
`increased binding and transport to cells.
`
`pa -1336926
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1020, p.06 of 10
`
`

`

`Application No.: 111553,339
`
`7
`
`Docket No.: 638772000301
`
`Example 48 fUlther demonstrates the production of a nanopalt icLe pharmaceutical
`
`composition with a starting albumin/pacl itaxel ratio of 4.5: I.
`
`Thus, a low album in/pharmaceut ical agen t ratio, such as the ratios recited in claims of the
`
`present application, allows enhanced cell ular binding and transport of th e pharmaceutical agent
`
`wh ile at the same ti me allowing the fOlmation of stable nanopm1icle compositions of the
`
`pharmaceutical agent even at the low ratio. Such advant ageous resu lt and characteristics were
`
`neither taught not' suggested in the cited references.
`
`The two references cited by the Examiner, namely, Damascell i and Ibrahim, are si lent about
`
`the weight ratio of albumin to pharmaceutical agent in the composi tions disclosed therein. They
`
`nei ther teach nor suggest the sign ificance of the albumin/ pharmaceutical agent ratio on cellular
`
`binding and transport. Nor do they teach 0 1' suggest that a low albumin/pharmaceutical agent ratio,
`
`such as those rec ited in the elaim:-; of the present appl ication, would all ow enhanced cellu lar binding
`
`and transp0l1 of the pharmaceutic al agent while at the same time allow ing the fOlmation of stable
`
`nanoparticle composi tions of the pharmaceutical agent even at low ratio.
`
`The Examiner acknowledges that Damaseelli does not disclose a specific albuminJpaclitaxel
`
`ratio, but states that "i t would have been obvious to one of ordin ary skill in the art at the time the
`
`invention was made to modi fy the teachings of Damascelli by determining the optimum
`
`concentration and/or weight ratio of al bumin to paclitaxel that will result in a composi tion that will
`
`deliver paclitaxel most effecti vely in an albumin del ivery system." App lica nts respectfu lly
`
`disagree.
`
`First, Damascelli is completely silent about any need or even desirabil it y to fUl1her mOdify
`
`the composition disclosed therein in order to delivery paclitaxel more effectively. According to
`
`Damasceili, intraarterial admini stration of ABlOO7 has "acceptable toxici ty" and at most dose levels
`
`"showed considerable antitumor activity (42 assessable patients with 80.9% complete response and
`pallia l response)." See Abstract. There is no indkation that deli very of paclitax el needs to or
`
`shou ld be further improved.
`
`pa -1336926
`
`Apotex v. Abraxis - IPR201 8-00153 , Ex. 1020, p.07 of 10
`
`

`

`Application No.: 111553,339
`
`8
`
`Docket No.: 638772000301
`
`Second, Damascelli provides no direction or basis for adjusting the weight ratio of albumin
`
`to pacl itaxel in the composition di sclosed therei n for the purpose of improving the composi tion, let
`
`alone any direction or basis fo r choosing a low albumin/pharmaceut ical agent ratio, such as the
`
`ratios recited in the present application.
`
`MPEP states,
`
`B. Only Result-Effecth'e Variables Can be Optimized
`
`A particular parameter must first be recognized as a result-effective variable, i.e., a variable
`which achieves a recognized result, before the determination of the optimum or workable
`range of said variable might be characteri zed as ro utine experimentation. In re Antonie, 559
`F.2d 618, 195 USPQ 6 (CePA I 977)(The claimed waste water treatment device had a lank
`volume to contractor area of 0. 12 gal/sq. ft. The prior an did not recognize that treatment
`capaci ty is a function of the tank vol ume to contractor ratio, and therefore the parameter
`optimized was not recognized in the mt to be a result-effective variable.). See also in re
`Boesch, 617 F.2d 272, 205 (CCPA 1980) (prior art sugges ted proportional balancing to
`achieve desired results in the formation of an alloy).
`
`MPEP §2 144.05. ll.B.
`
`As discussed above, Damascelli is silent about weight ratio of albumin to phannaceutical
`
`agent, namely, paditaxel, in the composition di sclosed therei n. Nor does Damaseelli teach or
`
`suggest the significance of the albumi n/pharmaceut ical agent ratio on cellu lar binding and transpOlt.
`
`Without a recogn ition in the alt of the significance of albumin/phannaceu tical agent rat io, for
`
`example in cellular binding and tmnsport of the pharmaceutical agent, one of ordin ary ski ll would
`
`not have been motivated to adjust the albumin/pharmaceutical agent ratio, let alone to choose a low
`
`albumin/pharmaceutical agent ratio, such as the ratios reci ted in the present application, in order to
`
`make a composition that will delivery the pharmaceutical agent most effectively in an albumin
`
`del ivery system.
`
`Similarly, Ibrahim neither di scloses a weight ratio of albumin to pharmaceutical agent nor
`
`teaches the significance of the albumin/pharmaceutical agent ratio on the cellular binding and
`
`tmnsp0l1.
`
`pa -1336926
`
`Apotex v. Abraxis - IPR201 8-00153 , Ex. 1020, p.08 of 10
`
`

`

`Application No.: 111553,339
`
`9
`
`Docket No.: 638772000301
`
`Because it has not been established that the weight ratio of albumin to pharmaceutical agent
`
`was recognized in the art as a result-effective variable, Applicants respectfully submit that the
`
`rejection of the claims should be withdrawn .
`
`Applicants further respectfu lly su bmit that optimization andlor achieving a desired result do
`
`not mean the result is non- inventive. As discussed above, the albumin/pharmaceutical agent ratios
`
`recited in claims of the present appl ication allow enhanced cellular binding and transpolt of the
`
`pharmaceutical agent while at the same time allowing the formatio n of stable nanoparticle
`
`compositions of the pharmaceu tical agent even at the low ratio. Such advantageous result and
`
`characteristics were neither predictable based on the teaching of the cited references nor expected by
`
`a person of ordinary skill in the rut.
`
`Accordingly, Appl icants respectfull y request that the rejection under 35 U.S.C. § 103(a) be
`
`withdrawn.
`
`pa -1336926
`
`Apotex v. Abraxis - IPR201 8-00153 , Ex. 1020, p.09 of 10
`
`

`

`Application No.: 111553,339
`
`10
`
`Docket No.: 63877200030 1
`
`CONCLUSION
`
`In view of the above, each of the presentl y pend ing claims in this application is believed
`
`to be in immediate condition for allowance. Accordingly, the Exam iner is respectfully requested to
`
`withdraw the outstanding rejection of the claims and to pass this application to issue. If it is
`
`determined that a telephone conference would expedite the prosecution of this application, the
`
`Examiner is in vited to telephone the unders igned at the number given below.
`
`In the event the U.S. Patent and Trademark office determines that an extension and/or
`
`other relief is required , applicant petition s for any required relief includi ng extensions of time and
`
`authorizes the Co mmissioner to charge the cost of such petitions and/or other fees due in connection
`
`with the fi li ng of this document to Deposit Account No. 03-1952 referencing docket no.
`
`638772000301. However, the Commissioner is not authorized to charge the cost of the issue fee to
`
`the Deposit Account.
`
`Dated: October 27, 2009
`
`Respectfull y subm itted,
`
`Electronic Signature: /Jian Xiaol
`Jian Xiao
`Registration No.: 55,748
`MORR ISON & FOERSTER LLP
`755 Page Mill Road
`Palo Alto, Cal iforn ia 94304- I a I 8
`(650) 813-5736
`
`pa -1336926
`
`Apotex v. Abraxis - IPR201 8-00153 , Ex. 1020, p.IO of 10
`
`