PATENT AND TRADE MARK ATTORNEYS
`
`GROSER & GROSER
`D-1/5, DLF QUTAB ENCLAVE, PHASE-I,
`GURGAON- 122002, INDIA
`
`TELEPHONE :
`
`0091-124- 4660500
`
`FSG: SRV: 2899/DELNP/2005
`
`TELEFAXES
`
`:
`
`0091-124- 4660522
`0091-124- 4660523
`
`0091-124- 4222364
`
`0091-124- 4222365
`
`E-mail
`
`:
`groser@vsni.com
`January 6, 2009
`Attention: Dr. ARCHANA GUPTA
`
`THE PATENT OFFICE
`
`THE CONTROLLER OF PATENTS
`
`DELHILens,ve
`a2,a’
`oo
`
`wt VERY URGENT
`
`
`: __-1SSiNAL DATE FOR ALLOWANCE:January 7, 2009
`
`
`Dear Sir,
`
`re:
`
`Abraxis BioScience, LLC
`Indian [National Phase] Patent Application No. 2899/DELNP/2005
`Filed: June 29, 2005
`Outof International Appin. No. PCT/US2003/038941 dated December9, 2003
`Priority date: December9, 2002 — United States Application No. 60/432,317
`December3, 2003 — United States Application No. 60/526544
`December4, 2003 — United States Application No. 60/526773
`December5, 2003 — United States Application No. 60/527177
`
`This response is made to the objections raised in the first examination report
`(FER).
`
`As a preliminary point, the applicants respectfully submit that the claims onfile
`have been revised and amendedto address each of the Examiner's objections in
`the first examination report as well as the points marked by her in pencil on the
`original claims. The amendments to the claims have necessitated re-typing pages
`47 to 56 as fresh pages 47 to 49 which are submitted herewith in duplicate
`together with the corresponding pages which have been cancelled over our
`signature.
`
`Eachof the objections is dealt with hereafter either individually or together with the
`other cognate objections.
`
`Objections 1, 14 and 15:
`
`With respect, the applicants submit that the claims as amended are novel and
`inventive over the prior art documentscited in the International Search Report and
`relied upon by the Examiner and thus, qualify as an invention.
`
`Actavis - IPR2017-01100, Ex. 1033, p. 1 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 1 of 12
`
`

`

`recites a sterile pharmaceutical composition comprising a
`As revised, claim 1
`water insoluble pharmaceutical agent and albumin, wherein the ratio (w/w) of
`albumin to pharmaceutical agent in the composition is 1:1 to 9:1, wherein the
`pharmaceutical composition comprises nanoparticles comprising the water
`insoluble pharmaceutical agent and albumin, and wherein the nanoparticles have
`a particle size of less than 200 nm.
`It is the applicants’ respectful submission that there is no teaching in the cited
`references that would lead to the claimed combination of the recited ingredients in
`the stated ratio in a sterile nanoparticle pharmaceutical composition. In the priorart,
`the focus was on using albumin to stabilize the water insoluble pharmaceutical
`agent in a nanoparticle composition and to avoid side effects caused by the
`administration of the water insoluble pharmaceutical agent. Because albumin is a
`macromolecule in nature and has a net negative charge, an increase in the
`amount of albumin would lead to higher viscosity and increased steric and
`electrostatic intermolecular repulsion — a favorable environment for nanoparticles.
`It was thus generally believed that a higher amount of albumin is desirable in
`order to keep the waterinsoluble pharmaceutical agent in a nanoparticle form.It
`was unexpected that a lower albumin/drug ratio (namely, 1:1 to 9:1) would
`maintain the water insoluble drug in a nanoparticle pharmaceutical composition,
`maintaining the many advantagesof a nanoparticle pharmaceutical composition.
`Albumin to drug ratio of 1:1 to 9:1 is more advantageous because it leads to
`enhanced cellular transport of the water insoluble pharmaceutical agent and
`reduces the adverse effects of albumin on the pharmacological activity of the
`water insoluble pharmaceutical agent, both of which would lead to improved
`therapeutic efficacy. A lowerratio is also important becauseit reduces safety risks
`caused by the administration of albumin. Not only that, a lower albumin/drug ratio
`is also economically significant because less albuminis neededin the formulation.
`Furthermore, a lower albumin/drug ratio provides manufacture efficiency because
`it reduces the viscosity problem during the large scale manufacturing process.
`
`Eachcitationis individually discussed hereafter:
`
`WO 92/07259 (D1):
`This reference discloses a pharmaceutical composition comprising a covalent
`adduct of deferoxamine, ferric iron, and polymer (such as albumin) for imaging
`enhancement. The reference does not disclose water
`insoluble drugs or
`nanoparticles comprising water insoluble pharmaceutical agent and albumin.
`Furthermore, D1 does not disclose an albumin/drug ratio as claimed, viz. albumin
`to drug ratio of 1:1 to 9:1.
`
`Meijs (D2):
`This reference discloses albumin-desferal conjugates for labeling protein with ion
`isotopes. D2 does not disclose water insoluble drugs or nanoparticles comprising
`water insoluble pharmaceutical agent and albumin. Furthermore, D2 does not
`disclose an albumin/drugratio as claimed, viz. albumin to drug ratio of 1:1 to 9:1.
`
`Actavis - IPR2017-01100, Ex. 1033, p. 2 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 2 of 12
`
`

`

`US 4,425,319 (D3):
`
`a
`deferoxamine,
`comprising
`agent
`diagnostic
`radioactive
`discloses
`D3
`physiologically active compound (such as albumin), and a radioactive metallic
`element chemically connected thereto. It nowhere discloses water insoluble drugs
`or nanoparticles comprising water insoluble pharmaceutical agent and albumin.
`Furthermore, D3 does not disclose an albumin/drug ratio as claimed, viz. albumin
`to drug ratio of 1:1 to 9:1.
`
`US 5,990,153 (D4):
`
`D4 discloses micelles of lipid-soluble antioxidants and lipoic acid in aqueous
`solutions (such as albumin solutions), which may also contain antioxidants and/or
`metal chelators
`(such as deferoxamine). However,
`it does not disclose
`nanoparticles comprising water insoluble pharmaceutical agent and albumin.
`Furthermore, D4 does not disclose an albumin/drug ratio as claimed, viz. albumin
`to drug ratio of 1:1 to 9:1.
`
`WO 2004/007520 (D5):
`
`This reference was cited in the International Search Report as only a “E”
`reference [Earlier document but published on or after the internationalfiling date].
`D5, therefore, does not qualify as valid prior art. In any event, this reference was
`cited against only former claims 37 to 50 directed to a method of inhibiting
`microbial growth or inhibiting oxidation by adding deferoxamine, and not as being
`relevant
`to the subject matter currently in the main composition claim. This
`reference discloses a method of preventing oxidative damage to proteins (such as
`albumin). D5 does not disclose nanoparticles comprising water
`insoluble
`pharmaceutical agent and albumin. Furthermore, D5 does not disclose an
`albumin/drug ratio as claimed, viz. albumin to drug ratio of 1:1 to 9:1.
`
`EP 0227593 (D6):
`
`This reference wascited against only former claims 37 to 50 directed to a method
`of inhibiting microbial growth or inhibiting oxidation by adding deferoxamine, and
`not as being relevant to the subject matter currently in the main composition claim.
`This reference discloses a method for treating cancer by administering iron
`chelating agents (such as deferoxamine) and a cytostatic agent. D6 does not
`disclose albumin or nanoparticles comprising water insoluble pharmaceutical
`agent and albumin. Furthermore, D6 does not disclose an albumin/drug ratio as
`claimed, viz. albumin to drug ratio of 1:1 to 9:1.
`
`FR 2775900 (D7):
`
`This reference wascited against only former claims 37 to 50 directed to a method
`of inhibiting microbial growth or inhibiting oxidation by adding deferoxamine, and
`not as being relevant to the subject matter currently in the main composition claim.
`D7 teaches the use of deferoxamine to prevent haematopoiteic and tissue toxicity
`of anthracyclines. It does not disclose albumin. Furthermore, D7 does not disclose
`an albumin/drug ratio as claimed, viz. albumin to drug ratio of 1:1 to 9:1.
`
`Actavis - IPR2017-01100, Ex. 1033, p. 3 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 3 of 12
`
`

`

`US 4,645,660 (D8):
`
`This reference wascited against only former claims 37 to 50 directed to a method
`of inhibiting microbial growth orinhibiting oxidation by adding deferoxamine, and
`not as being relevant to the subject matter currently in the main composition claim.
`D8 discloses non-radioactive
`carrier
`for
`increasing labeling efficiency of
`radioactive
`diagnostic
`agent
`comprising
`a
`carrier
`substance
`having
`a
`chelate-forming property (such as deferoxamine) and optionally a physiologically
`active substance chemically bonded thereto (such as albumin). D8 does not
`disclose nanoparticles comprising water
`insoluble pharmaceutical agent and
`albumin. Furthermore, D8 does not disclose an albumin/drug ratio as claimed, viz.
`albumin to drug ratio of 1:1 to 9:1.
`
`Halliwell (D9):
`
`This reference was cited in the International Search Report as only a ‘A’
`reference relevant only to claims 37 to 50 directed to a method of inhibiting
`microbial growth orinhibiting oxidation by adding deferoxamine, and not as being
`relevant
`to the subject matter currently in the main composition claim. This
`reference is only a category “A”citation, which implies that this documentdefines
`merely the general state of art but is not considered to be of particular relevance.
`D9 discloses the use of deferoxamine as an inhibitor of iron-dependent free
`radical reactions.
`It does not disclose water insoluble drugs or nanoparticles
`comprising water insoluble pharmaceutical agent and albumin. Furthermore, D9
`does not disclose an albumin/drug ratio as claimed, viz. albumin to drug ratio of
`1:1 to 9:1.
`
`Chuang
`
`(D10):
`
`D10 is a review article which discusses different methodologies of using albumin
`for drug delivery. Although D10 generally discloses microspheres,
`it does not
`disclose an albumin/drug ratio as claimed, viz. albumin to drug ratio of 1:1 to 9:1 in
`a sterile nanoparticle pharmaceutical composition.
`
`US 5,916,596 (D11):
`
`D11 is a patent owned by Abraxis BioScience, LLC, the applicant of the instant
`case. This reference reflects Applicants’ prior effort in formulating water insoluble
`pharamceutical agents by eliminating physiologically harmful organic solvents.
`This
`reference does
`not disclose
`a
`sterile nanoparticle pharmaceutical
`composition having an albumin to drug ratio as claimed, viz. albumin to drug ratio
`of 1:1 to 9:1.
`
`US 5,439,686 (D412):
`
`D12 is a patent owned by Abraxis BioScience, LLC, the applicant of the instant
`case. This reference reflects Applicants’ prior effort in formulating water insoluble
`pharamceutical agents by eliminating physiologically harmful organic solvents.
`This
`reference does
`not disclose
`a_
`sterile nanoparticle pharmaceutical
`composition having an albumin to drug ratio as claimed, viz. albumin to drug ratio
`of 1:1 to 9:1.
`
`Actavis - IPR2017-01100, Ex. 1033, p. 4 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 4 of 12
`
`

`

`WO 00/23117 (D13):
`
`D13 discloses a conjugate (a single component) of photosensitizer and a targeting
`moiety (moiety can be “aggregated albumin’, or albumin).
`It, however, does not
`disclose nanoparticles comprising water
`insoluble pharmaceutical agent and
`albumin. Furthermore, D13 does not disclose an albumin/drug ratio as claimed,
`viz. albumin to drug ratio of 1:1 to 9:1.
`
`EP 0544292 (D14):
`
`D14 discloses a non-covalent complex of nucleic acid and protein for delivery of
`nucleic acid. It does not disclose the use of water insoluble drugs and/or albumin.
`Furthermore,
`it does not
`teach nanoparticles
`comprising water
`insoluble
`pharmaceutical agent and albumin.
`
`US 6310039 (D15):
`
`D15 discloses a single pharmaceutical agent, namely, a conjugate of a cytostatic
`compound (such as paclitaxel) and albumin.
`It does not disclose nanoparticles
`comprising water insoluble pharmaceutical agent and albumin. Nor does the
`reference disclose a combination of a water insoluble pharamceutical agent and a
`pharamceutically acceptable carrier comprising albumin.
`
`US 6204054 (D16):
`
`D16 discloses transcytosis vehicles and enhancers (such as albumin) capable of
`delivering and enhancing drug transport via GP60. The drugs exemplified in the
`description of this reference are all water soluble drugs. According to D16, a
`composition can be formulated into microcapsules of 2-5 microns. D16 does not
`disclose nanoparticles having a particle size of less than 200 nm. Nor doesit
`disclose an albumin/drugratio as claimed, viz. albumin to drug ratio of 1:1 to 9:1.
`
`To anticipate a patent, a prior publication must contain the whole of the invention
`impugned, i.e. all the features by which the claims in question are limited.
`It
`is
`clear from the foregoing discussion that noneof the cited references discloses the
`claimed combination of the recited ingredients in the stated ratio in a sterile
`pharmaceutical composition. Thus, the present claims are not anticipated by the
`cited priorart.
`
`The applicants further submit that claims as amendedare inventive over the cited
`references.
`In order to uphold a finding of lack of inventiveness, there must be
`some teaching, suggestion or incentive for doing what the applicants have done.
`Typically, both the suggestion and the expectation of success must be found in
`the prior art, not in the applicants’ disclosure. A prima facie case of obviousness
`can be established only by showing someobjective teaching in the prior art or by
`proving that knowledge generally available to a person skilled in the relevant art
`would lead the individual to combine relevant teachingsof the prior references.
`
`As stated above, claims have been amendedto recite a sterile pharmaceutical
`composition comprising a water insoluble pharmaceutical agent and albumin,
`
`Actavis - IPR2017-01100, Ex. 1033, p. 5 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 5 of 12
`
`

`

`wherein the ratio (w/w) of albumin to pharmaceutical agent in the composition is
`1:1 to 9:1, wherein the pharmaceutical composition comprises nanoparticles
`comprising the water insoluble pharmaceutical agent and albumin, and wherein
`the nanoparticles have a particle size of less than 200 nm. Noneof the cited
`references discloses the claimed composition. In the cited prior art, focus was on
`the function of albumin for stabilizing water insoluble drug in nanoparticles and
`reducing side effects.
`In that regard, a higher albumin to drug ratio would be
`preferred (The more albumin the more likely water insoluble drug is stabilized). \t
`was unexpected from prior art that a lower albumin/drug ratio (namely, 1:1 to 9:1)
`would allow the water
`insoluble drug be in a nanoparticle pharmaceutical
`composition, maintaining the many advantages of a nanoparticle pharmaceutical
`composition.
`
`Example 46 in the description demonstrates that lower amounts of albumin in the
`inventive pharmaceutical
`composition
`results
`in
`stable
`compositions. To
`investigate if lower amounts of albumin in the composition would affect stability of
`the inventive pharmaceutical composition, albumin-paclitaxel compositions with
`low amounts of albumin were prepared.
`It was found that these compositions
`were as stable as compositions with higher quantities of albumin when examined
`for several monthsat different temperatures (2-8 °C, 25 °C, and 40 °C) for potency
`of paclitaxel, 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.
`In this regard, Example 48 further demonstrates that a nanoparticle formulation of
`paclitaxel can be madeat an albumin/paclitaxel ratio of 4.5:1 (w/w).
`
`is clear from a review of the examples presented in the specification for this
`It
`application that nanoparticle formulation of water
`insoluble drug is more
`efficacious.
`
`The lowerratio recited in the claims involves technical advance as compared to the
`existing knowledge.
`
`A lower albumin/drug ratio as claimed in the revised main claim allows enhanced
`cellular transport.
`
`Paragraph [0041] of the present specification (see page15) states as follows:
`
`“...Not to adhere to any oneparticular theory,it is believed that the ratio of protein,
`e.g., human serum albumin,
`to pharmaceutical agent
`in the pharmaceutical
`composition affects the ability of the pharmaceutical agent to bind and transport
`the pharmaceutical agent to a cell.
`In this regard, higher ratios of protein to
`pharmaceutical agent generally are associated with poor cell binding and
`transport of the pharmaceutical agent, which possibly is the result of competition
`for receptors at the cell surface. The ratio of protein, e.g., albumin,
`to active
`pharmaceutical agent must be such that a sufficient amount of pharmaceutical
`agentbindsto, or is transportedby, the cell...”
`
`Example 45 demonstrates that increasing amounts of albumin can compete with
`binding of paclitaxel to immobilized albumin and endothelial cells. Albumin was
`immobilized on a microtiter plate. Fluorescent paclitaxel was addedinto the wells
`
`Actavis - IPR2017-01100, Ex. 1033, p. 6 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 6 of 12
`
`

`

`and the binding of paclitaxel was measured using a scanning fluorometer.
`Increasing amounts of albumin was addedto the wells andthe levelof inhibition of
`paclitaxel binding to immobilized albumin was measured. The data showedthat
`as the amount of albumin added was increased, a corresponding decrease in
`binding was seen. A similar effect was seen with binding to endothelial cells. This
`indicated that higher albumin concentration inhibited binding of paclitaxel. Thus,
`invention compositions having lower amounts of albumin are preferred.
`
`A high albumin/drug ratio not only affects the cellular transport of the water
`insoluble pharmaceutical agent but also leads to an increased local concentration
`of albumin at the tumour site. In this regard, paragraphs [0045] and [0048] of the
`description (see page 16)state ,
`
`[0045]
`
`[0048]
`
`“Tumor cells exhibit an enhanced uptake of proteins including, for example,
`albumin and transferring, as compared to normal cells. Since tumor cells are
`dividing at a rapid rate,
`they require additional nutrient sources compared to
`normal cells.
`Tumor studies of the inventive pharmaceutical compositions
`containing paclitaxel and human serum albumin showedhigh uptake of albumin-
`paclitaxel
`into tumors.
`This has been found to be due to the previously
`unrecognized phenomenon of the albumin-drug transport by glycoprotein 60
`(“gp60”) receptors, which are specific for albumin.”
`
`the transport of a protein-drug
`“Without being bound to any particular theory,
`composition by receptor-mediated transport resulting in a therapeutic effect is
`believed to be the mechanism for transport of for example, albumin-paclitaxel
`compositions to a tumor, as well as albumin-paclitaxel and albumin-rapamycin
`transport across the lung. Transport is effected by the presence of gp60, gp16, or
`gp30 in such tissues....”
`
`Thus, when the pharmaceutical composition comprises albumin and drug at a
`high
`ratio, more free albumin would compete with
`the water
`insoluble
`pharmaceutical
`agent
`for
`receptor
`binding,
`resulting
`in
`increased
`local
`concentration of albumin at the tumor site. An increased local concentration of
`albumin at the tumor site would adversely affect the pharmacological function of
`the water insoluble pharmaceutical agent. In contrast to this, a lower albumin/drug
`ratio, namely albumin/drug ratio of 1:1 to 9:1, would reduce the adverse effects of
`albumin on the pharmacological activity of the water insoluble pharmaceutical
`agent and thus, leads to an improved therapeutic efficacy.
`
`A lower albumin/drug ratio also shows
`pharmaceutical formulation.
`
`improved safety profile of
`
`the
`
`Albumin, which accounts for 70-80% colloid osmotic pressure in the plasma, is the
`main determinant of plasma osmotic pressure and plays a pivotal
`role in
`modulating the distribution of fluids between compartments.
`
`Actavis - IPR2017-01100, Ex. 1033, p. 7 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 7 of 12
`
`

`

`It is clear that infusion of albumin at a high concentration would alter the osmotic
`pressure of the plasma which in turn would reduce hemoconcentration and
`decrease blood viscosity,
`thereby resulting in undesirable adverse effects of
`albumin in the pharmaceutical composition.
`
`The lowerratio recited in the claims also has great economic significance.
`
`The fair market value of HSA is about $ 4/gram. Reducing the amount of albumin
`in the nanoparticle formulation would reduce the manufacturing cost. Lowering the
`albumin/drug ratio facilitates scale-up production of nanoparticles. Albumin causes
`viscosity problem and makesit difficult for scale-up manufacture. Reducing the
`amount of albumin in the pharmaceutical formulation would reduce the viscosity
`problem andfacilitate the manufacture process.
`
`from the arguments and submissions presented
`is unequivocally clear
`It
`hereinabove that the novel and inventive pharmaceutical composition claimed in
`the present application not only maintains the many advantagesof a nanoparticle
`formulation of water
`insoluble pharmaceutical agents but also provides an
`increased therapeutic efficacy, an improved safety profile, and great economic
`significance, such as reduced costs and increased manufacture efficiency.
`
`On thorough comparison, it will be found that the cited prior art neither discloses
`the novel and inventive combination of claim 1 of the present invention nor the
`advantages associated with such a combination.
`It
`is submitted with all
`the
`emphasis at the applicants’ command that no pointer could be identified in the
`cited prior art that use of the recited ingredients in the claimed combinatorial ratio
`could result
`in such a pharmaceutical composition which will produce the
`significant technical advantages recited above.
`
`To substantiate our arguments, we submit herewith a declaration from one of the
`eight inventors responsible for this application, namely Vuong Trieu, which clearly
`shows how the claimed pharmaceutical composition of
`the revised claims
`constitutes a technical advance over the cited documents.
`
`The unexpected properties shown by the formulation of the present invention
`would clearly not be predictable based on the teachings of the documentscited in
`the ISR and relied upon by the Examiner whether considered alone or
`in
`combination with each other.
`It
`is reiterated that none of the cited prior art
`documents discloses the features of the revised claims being submitted herewith
`and consequently the revised claims are novel and inventive over the cited
`documents.
`It
`is emphasized that from the teachings of the cited documents, a
`skilled addressee could not have arrived at
`the invention of
`the present
`application.
`
`In view of the amendments effected and submissions presented, it is believed that
`the claims of the present invention are novel and clearly involve an inventive step
`within the meaning of Section 2 (1) (ja) and thus, constitute an invention as
`defined under Section 2 (1) (j) of our Patents Act, 1970. Accordingly, waiverof the
`objections in paragraphs 1, 14 and 15 is respectfully requested.
`
`Actavis - IPR2017-01100, Ex. 1033, p. 8 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 8 of 12
`
`

`

`Objections 2 and 3:
`
`It is respectfully submitted that the requirements in these paragraphs have no
`relevance under the present patent scenario. With so many repositories of
`foreign documents throughout India and world not to mention the basic source
`thereof, namely the Internet, any readerof Indian specification can quite easily
`have access to any foreign patent or published application. Accordingly, the
`requirements in these paragraphs should be withdrawn.
`
`Objections 4 to 6 and 8:
`
`The revised claims being submitted herewith are clearly worded andsufficiently
`definitive.
`
`Claims as amended have only one independent claim geared to a sterile
`pharmaceutical composition. The revised main claim now identifies all
`the
`essential ingredients of the claimed composition and explicitly states the unique
`ratio between the recited components.
`
`All the redundant claims have been deleted and the claims as revised do not
`involve any unnecessary repetition.
`
`The dependencyclauses in the sub-claims have been altered to “as claimedin”
`instead of “of”.
`
`Objection 7:
`
`To meet the requirementin this paragraph, the title has been revised to bring it
`into verbal conformity with the preamble to the main claim. The revisedtitle reads
`as follows:
`
`“STERILE PHARMACEUTICAL COMPOSITION”
`
`The revisedtitle has been incorporated into the first page of Application Form 1
`and cover page to the specification (Form 2), which are submitted herewith in
`duplicate.
`
`Objections 9 to 11:
`
`The amendments carried out to the claims take into account the objection of
`distinct inventions.
`
`The replacement set of claims being submitted herewith comprises a single
`independent claim directed to a sterile pharmaceutical composition followed by a
`set of dependent sub-claims.
`
`Actavis - IPR2017-01100, Ex. 1033, p. 9 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 9 of 12
`
`

`

`Objection 12:
`
`Section 3 (i) bars the patentability only of methods which relate essentially to the
`treatment of a live subject for the purpose of curing such subject of a disease or
`increasing its economic value orthat of its products.
`
`In view of the Examiner's objection, the “method of treatment” claims have been
`deleted from the current specification. As revised, the claims are directed only to a
`sterile pharmaceutical composition per se. Any future use of
`the claimed
`composition in any method of treatment of humans and/or animals does not form
`part of the claimed subject matter. Withdrawal of the objection in this paragraphis,
`therefore, respectfully requested.
`
`Objection 13:
`
`As revised, claim 1 specifically recites nanoparticles and the ratio of albumin and
`the water insoluble pharmaceutical agent.
`
`is clear from the foregoing submissions that the claimed combination of the
`It
`ingredients in the unique combinatorial ratio provides surprising and unexpected
`advantages and, therefore, the claimed combination is not a mere admixture of
`the recited ingredients.
`
`the the combination of the recited
`invention demonstrates that
`The present
`ingredients in the unique (claimed) combinatorial ratio, namely 1:1 to 9:1, would
`unexpectedly allow the water insoluble pharmaceutical agent be stabilized in a
`nanoparticle pharmaceutical composition [see Examples 46 and 48 discussed
`above]. Not only that, the claimed combination of the ingredients in the special
`ratio recited in the revised main claim leads to enhancedcellular transport (and
`reduces undesirable adverse effects of albumin) which in turn leads to improved
`therapeutic efficacy of the water insoluble drug [see Example 45 discussed
`above]. The combination of albumin and the water insoluble pharmaceutical agent
`in the lower ratio as claimed strikingly produces a better safety profile which in
`turn translates into efficacy.
`
`this
`the working examples presented in the specification for
`A review of
`application (discussed above) clearly shows that the claimed composition has
`both enhanced properties in terms of efficacy and is more than an admixture
`evincing only an aggregation of the properties of the individual components. In the
`examples disclosed in the present specification and discussed in the foregoing
`paragraphs,
`it
`is demonstrated that the combination of albumin and the water
`insoluble pharmaceutical agent
`in
`the claimed ratio is
`significant
`from a
`performance perspective.
`
`The claimed combination of ingredients in the unique combinatorial ratio exhibits
`significant efficacy and unexpectedly improved performance. It is evidently clear
`from our comments in the preceding paragraphs that the composition of the
`presentinvention is not a mere admixture of components and, therefore, does not
`attract the prohibition contained under Section 3 (e).
`
`Actavis - IPR2017-01100, Ex. 1033, p. 10 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 10 of 12
`
`

`

`Withdrawal of this objection is, therefore, respectfully requested.
`
`Objections 16 and 21:
`
`The requirement in paragraph 16 has already been complied with by virtue of the
`submission of Forms 3 dated June 29, September 15 and December 30, 2005
`and July 8, 2008.
`
`We now submit in duplicate petitions under Rules 137 and 138 together with the
`prescribed fee for obviating the irregularity and requesting an extension of time in
`respect of Forms 3 submitted in respect of this application. This complies with the
`requirementin paragraph 21.
`
`Objection 17:
`
`The statutory requirement under Section 8 (2) of our law raised in paragraph 17
`has already been met through the submission of the copies of the office actions
`issued in respect of the corresponding US patent applications under cover of our
`letter of July 7, 2008.
`
`Additionally, we submit herewith the following documents:
`
`(1)
`
`A-copy of the office action dated April 24, 2008 issued in respect of US
`Application No. 10/731,224;
`
`(2)|Acopyofthe office action dated May 12, 2008 issued in respect of US
`Application No. 11/553,339;
`
`(3)|A copyofthe office action dated October 10, 2008 issued in respectof
`US Application No. 11/553,339;
`
`(4)
`
`Acopy ofthe office action dated March 28, 2008 issued in respect of
`US Application No. 11/553,350; and
`
`(5)|Acopyof the office action dated December 1, 2008 issued in respect of
`US Application No. 11/553,350.
`
`Objections 18 and 19:
`
`We have the honour to submit herewith in duplicate a fresh Application Form 1
`and Form 5 incorporating the name of the current applicants and the full name of
`the first named inventor.
`
`The superseded forms have been duly cancelled over our signature and are being
`returned herewith.
`
`Actavis - IPR2017-01100, Ex. 1033, p. 11 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 11 of 12
`
`

`

`Objection 20:
`
`This objection has already been met through the submission of a copy of the Form
`PCT/IB/304 and a certified copy of the second priority application, viz. US
`Application No. 60/526544.
`
`We now havethe honour to submit herewith in duplicate a petition under Rule 137
`together with the prescribed fee for obviating the irregularity in the submission of
`the said certified copy.
`
`Objection 22:
`
`Wehave the honour to submit herewith a fresh abstract in duplicate.
`
`Based on the amendments effected and arguments and submissions presented
`herein, it is believed that this application is in order.
`
`Accordingly, allowance thereof
`deadline of January 7, 2009.
`
`is
`
`respectfully requested by the prescribed
`
`In case the Examiner is not convinced of the allowability of the present claims,
`oral hearing is requested before the final disposal of this application.
`
`Yoursfaithfully,
`
`a
`
`Shalu Ran Vijay
`of Groser & Groser
`Agentfor the Applicants
`
`Enclosures:
`Returned endorsed Application Form 1;
`Application Form 1 in duplicate;
`Cancelled Application Form 1;
`Form 5 in duplicate;
`Cancelled Form 5;
`Retuned complete specification;
`Retyped pagesin duplicate;
`Cancelled pages;
`Abstract in duplicate;
`Cancelled abstract;
`Declaration from inventor;
`Petition under Rule 137 in duplicate;
`Petitions under Rules 137 and 138 in duplicate;
`Copies of US office actions
`
`Herewith Rs. 12000. 00
`
`Actavis - IPR2017-01100, Ex. 1033, p. 12 of 12
`
`Actavis - IPR2017-01100, Ex. 1033, p. 12 of 12
`
`