IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re A
`
`lication of:
`
`Inventor(s):
`
`Sundaram, Srikanth, et al.
`
`Docket No.:
`
`009423.0l0USl
`
`App. No.:
`
`15/958,854
`
`Conf. No.:
`
`1051
`
`Filed: 2018-04-20
`
`Art Unit:
`
`1615
`
`Title: Storage Stable Sincalide Formulations
`
`Examiner:
`
`AL-AW ADI, DAN AH J.
`
`VIAEFS-WEB
`
`AMENDMENT & RESPONSE TO NON-FINAL OFFICE ACTION
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`
`Attention: Commissioner for Patents:
`
`The following amendments and remarks are submitted in response to the November 19,
`
`2018 Office Action. This paper is being submitted on or before February 19, 2019, thereby
`
`making this a timely response.
`
`Amendments to the Specification begins on page 2 of this paper.
`
`Amendments to the Claims are reflected in the listing of claims that begins on 5 of this
`
`paper.
`
`Remarks begin on page 12 of this paper.
`
`Bracco Ex. 2013
`Maia v. Bracco
`IPR2019-00345
`
`1
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`Amendments to the Specification
`
`Please replace paragraph [0043] with the following amended paragraph:
`
`[0043] A surfactant/solubilizer is used to generally reduce the interfacial tension or aid in
`
`solubilization thus preventing or reducing denaturation and/or degradation at air/liquid or
`
`liquid/solid interfaces of a peptide in solution. As described herein, the compositions
`
`comprise sincalide, lack a buffer in solid form or optionally lack a buffer in liquid form,
`
`and optionally also lack a surfactant/solubilizer. Accordingly, as described herein, the
`
`compositions may comprise sincalide and a surfactant/solubilizer,_and lack a buffer. In
`
`some embodiments, a composition described herein comprises sincalide and optionally a
`
`surfactant/solubilizer, is storage stable, and lacks a buffer, e.g., dibasic potassium
`
`phosphate. A surfactant/solubilizer as described herein may be selected from the group
`
`consisting of free fatty acids; esters of fatty acids with polyoxyalkylene compounds like
`
`polyoxypropylene glycol and polyoxyethylene glycol; ethers of fatty alcohols with
`
`polyoxyalkylene glycols; esters of fatty acids with polyoxyalkylated sorbitan; soaps;
`
`glycerol-polyalkylene stearate; glycerol-polyoxyethylene ricinoleate; homo- and
`
`copolymers of polyalkylene glycols; polyethoxylated soya-oil and castor oil as well as
`
`hydrogenated derivatives; ethers and esters of sucrose or other carbohydrates with fatty
`
`acids, fatty alcohols, these being optionally polyoxyalkylated; mono-, di- and
`
`triglycerides of saturated or unsaturated fatty acids; glycerides or soya-oil and sucrose;
`
`sodium caprolate; ammonium sulfate; sodium dodecyl sulfate (SDS); Triton-I 00 and
`
`anionic surfactants containing alkyl, aryl or heterocyclic structures; and any combination
`
`thereof. In some embodiments, a composition as described herein comprises sincalide, is
`
`storage stable, lacks a buffer (e.g., dibasic potassium phosphate) and comprises or lacks a
`
`surfactant/solubilizer selected from the group consisting of a pluonic (e.g., Lutrol F68,
`
`Lutrol Fl27), Poloxamers, SDS, Triton-100, polysorbates such as TWEEN® 20 and
`
`TWEEN® 80, propylene glycol, PEG and similar compounds, Brij58 (polyoxyethylene
`
`20 cetyl ether), cremophor EL, cetyl trimethylammonium bromide (CTAB),
`
`dimethylacetamide (DMA), NP-40 (Nonidet P-40), and N-methyl-2-pyrrolidone
`
`(Pharmasolve ), glyeiae aad other am:iao aeids/am:iao aeid salts aad anionic surfactants
`
`2
`
`2
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`containing alkyl, aryl or heterocyclic structures, and cyclodextrins. In some
`
`embodiments, a composition as described herein comprises sincalide, is storage stable,
`
`lacks a buffer (e.g., dibasic potassium phosphate) and comprises or lacks a
`
`surfactant/solubilizer, wherein the surfactant/solubilizer is a polysorbate. In some
`
`embodiments, a solid composition as described herein comprises sincalide, is storage
`
`stable, lacks a buffer (e.g., dibasic potassium phosphate), and lacks or comprises a
`
`surfactant/solubilizer, wherein the surfactant/solubilizer is a polysorbate 20.
`
`A clean copy of paragraph [0043] is provided below:
`
`[0043] A surfactant/solubilizer is used to generally reduce the interfacial tension or aid in
`
`solubilization thus preventing or reducing denaturation and/or degradation at air/liquid or
`
`liquid/solid interfaces of a peptide in solution. As described herein, the compositions
`
`comprise sincalide, lack a buffer in solid form or optionally lack a buffer in liquid form,
`
`and optionally also lack a surfactant/solubilizer. Accordingly, as described herein, the
`
`compositions may comprise sincalide and a surfactant/solubilizer, and lack a buffer. In
`
`some embodiments, a composition described herein comprises sincalide and optionally a
`
`surfactant/solubilizer, is storage stable, and lacks a buffer, e.g., dibasic potassium
`
`phosphate. A surfactant/solubilizer as described herein may be selected from the group
`
`consisting of free fatty acids; esters of fatty acids with polyoxyalkylene compounds like
`
`polyoxypropylene glycol and polyoxyethylene glycol; ethers of fatty alcohols with
`
`polyoxyalkylene glycols; esters of fatty acids with polyoxyalkylated sorbitan; soaps;
`
`glycerol-polyalkylene stearate; glycerol-polyoxyethylene ricinoleate; homo- and
`
`copolymers of polyalkylene glycols; polyethoxylated soya-oil and castor oil as well as
`
`hydrogenated derivatives; ethers and esters of sucrose or other carbohydrates with fatty
`
`acids, fatty alcohols, these being optionally polyoxyalkylated; mono-, di- and
`
`triglycerides of saturated or unsaturated fatty acids; glycerides or soya-oil and sucrose;
`
`sodium caprolate; ammonium sulfate; sodium dodecyl sulfate (SDS); Triton-I 00 and
`
`anionic surfactants containing alkyl, aryl or heterocyclic structures; and any combination
`
`thereof. In some embodiments, a composition as described herein comprises sincalide, is
`
`3
`
`3
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`storage stable, lacks a buffer (e.g., dibasic potassium phosphate) and comprises or lacks a
`
`surfactant/solubilizer selected from the group consisting of a pluonic (e.g., Lutrol F68,
`
`Lutrol Fl27), Poloxamers, SDS, Triton-100, polysorbates such as TWEEN® 20 and
`
`TWEEN® 80, propylene glycol, PEG and similar compounds, Brij58 (polyoxyethylene
`
`20 cetyl ether), cremophor EL, cetyl trimethylammonium bromide (CTAB),
`
`dimethylacetamide (DMA), NP-40 (Nonidet P-40), and N-methyl-2-pyrrolidone
`
`(Pharmasolve ), anionic surfactants containing alkyl, aryl or heterocyclic structures, and
`
`cyclodextrins. In some embodiments, a composition as described herein comprises
`
`sincalide, is storage stable, lacks a buffer (e.g., dibasic potassium phosphate) and
`
`comprises or lacks a surfactant/solubilizer, wherein the surfactant/solubilizer is a
`
`polysorbate. In some embodiments, a solid composition as described herein comprises
`
`sincalide, is storage stable, lacks a buffer (e.g., dibasic potassium phosphate), and lacks
`
`or comprises a surfactant/solubilizer, wherein the surfactant/solubilizer is a polysorbate
`
`20.
`
`4
`
`4
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`Amendments to the Claims:
`
`This listing of claims will replace all prior versions and listings of claims in the
`
`application.
`
`1.
`
`(Currently Amended) A solid composition comprising sincalide, wherein the composition
`
`comprises a pH of about 6 to about 8 when reconstituted in a pharmaceutically acceptable
`
`diluent,
`
`wherein the composition does not contain a dibasie potassium phosphate buffer, and
`
`wherein the composition is stable in storage.
`
`2.
`
`(Currently Amended) The solid composition of claim 1, wherein the composition does
`
`not contain aHyphosphate buffer and also does not contain a buffer selected from the group
`
`consisting of phosphoric acid, citric acid, citrate, sulfosalicylate, acetic acid, acetate, methyl
`
`boronic acid, boronate, disodium succinate hexahydrate, lactic acid, lactate, maleic acid, maleate,
`
`potassium chloride, benzoic acid, sodium benzoate, carbonic acid, carbonate, bicarbonate, boric
`
`acid, sodium borate, sodium chloride, succinic acid, succinate, tartaric acid, tartrate,
`
`tris-(hydroxymethy 1 )aminomethane, N-2-hydroxyethy 1 pi perazine, N' -2-ethanesulfoni c acid
`
`(HEPES), CHAPS, and any combination thereof.
`
`3.
`
`(Currently Amended) The solid composition of claim +i, wherein the composition also
`
`does not contain polysorbate 20 and/or polysorbate 80.
`
`4.
`
`(Currently Amended) The solid composition of claim +i, wherein the composition dees-
`
`Hot eoHtaiH aHy surfaetaHt1solubiliz,erfurther comprises
`
`(a) at least one stabilizer,
`
`(b) at least one bulking agent/tonicity adjuster,
`
`(c) at least one chelator, or
`
`(d) any combination of (a)-(c).
`
`5.
`
`(Currently Amended) The solid composition of claim 1, wherein the composition does
`
`5
`
`5
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`not contain dibasic potassium.§: phosphate buffer and does not contain either or both polysorbate
`
`20 and/or polysorbate 80.
`
`6.
`
`(Currently Amended) The solid composition of claim 1, wherein the composition further
`
`compnses
`
`(a) at least one stabilizer,
`
`(b) at least one bulking agent/tonicity adjuster,
`
`(c) at least one chelator, or
`
`(d) any combination of (a)-(c)a stabilizer and/or a bulking agentltonicity adjuster.
`
`7.
`
`(Original) The solid composition of claim 6, wherein the stabilizer is selected from the
`
`group consisting of pentetic acid, arginine hydrochloride, L-methionine, L-lysine hydrochloride,
`
`sodium metabisulfite, and a combination thereof, and
`
`wherein the bulking agent/tonicity adjuster comprises mannitol.
`
`8.
`
`(Original) The solid composition of claim 1, wherein the composition maintains total
`
`impurities of less than 5% and/or a sincalide level of at least 90% after 15 months of storage at
`
`25°C, 60% relative humidity when tested by a sincalide-specific assay.
`
`9.
`
`(Previously Presented) The solid composition of claim 1, comprising:
`
`(a) a therapeutically effective amount of sincalide,
`
`(b) 1 to 4 mg pentetic acid,
`
`( c) 15 to 45 mg arginine hydrochloride,
`
`(d) 2 to 8 mg methionine,
`
`(e) 7.5 to 30 mg lysine hydrochloride,
`
`(f) 0.02 to 1 mg sodium metabisulfite,
`
`(g) 85 to 340 mg mannitol, and
`
`(e) a pH from 6.5 to 7.5 when reconstituted in a pharmaceutically acceptable diluent; and
`
`wherein the composition does not contain a buffer having a pKa within one unit of the pH.
`
`6
`
`6
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`10.
`
`(Original) The solid composition of claim 1, wherein the composition is a lyophilized
`
`powder.
`
`11.
`
`(Withdrawn) A method for the treatment, prevention, and/or diagnosis of gall bladder-
`
`and/or pancreatic disorders, or other diagnostic imaging of a patient in need thereof comprising
`
`administering a therapeutically or diagnostically effective amount of the composition of claim 1
`
`in reconstituted form to the patient.
`
`12.
`
`(Withdrawn) The method of claim 11, wherein the composition comprises:
`
`(a) a chelator comprising pentetic acid,
`
`(b) a stabilizer comprising a combination of L-arginine hydrochloride, L-methionine, L(cid:173)
`
`lysine hydrochloride, and sodium metabisulfite,
`
`( c) a bulking agent/tonicity adjuster comprising mannitol, and
`
`wherein the composition further lacks dibasic potassium phosphate, and wherein the composition
`
`further lacks polysorbate 20.
`
`13.
`
`(Withdrawn-Currently Amended) A method of making the storage stable solid sincalide
`
`composition of claim 1 comprising:
`
`(1) mixing:
`
`(a) sincalide, and
`
`(b) an excipient consisting essentially of (i) a stabilizer, (ii) a bulking
`
`agent/tonicity adjuster, (iii) a chelator, or (iv) any combination of (i), (ii) and (iii), and
`
`(c) water
`
`(2) adjusting the pH of the mixture to e-:-.§.about 6 to +:-.§.about 8, and
`
`(3) lyophilizing the pH-adjusted mixture,
`
`wherein the storage stable sincalide composition does not contain a phosphate buffer having a
`
`pKa within one unit of the pH.
`
`14.
`
`(Withdrawn-Currently Amended) The method of claim 13, wherein the storage stable
`
`solid sincalide composition does not contain a phosphate buffer and also does not contain a
`
`7
`
`7
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`buffer selected from the group consisting of phosphoric acid, citric acid, citrate, sulfosalicylate,
`
`acetic acid, acetate, methyl boronic acid, boronate, disodium succinate hexahydrate, lactic acid,
`
`lactate, maleic acid, maleate, potassium chloride, benzoic acid, sodium benzoate, carbonic acid,
`
`carbonate, bicarbonate, boric acid, sodium borate, sodium chloride, succinic acid, succinate,
`
`tartaric acid, tartrate, tris-(hydroxymethyl)aminomethane, N-2-hydroxyethylpiperazine, N'-2-
`
`ethanesulfonic acid (HEPES), CHAPS, and any combination thereofa surfaetaHt1solubiliz,er.
`
`15.-30. (Cancelled)
`
`31.
`
`(Previously Presented) The solid composition of claim 9, wherein the composition is a
`
`lyophilized powder.
`
`32.
`
`(Previously Presented) The solid composition of claim 31, wherein the composition
`
`maintains total impurities of less than 5% and/or a sincalide level of at least 90% after 15 months
`
`of storage at 25°C, 60% relative humidity when tested by a sincalide-specific assay.
`
`33.
`
`(Previously Presented) The solid composition of claim 31, wherein the composition
`
`maintains total impurities of less than 4% and/or a sincalide level of at least 90% after 15 months
`
`of storage at 25°C, 60% relative humidity when tested by a sincalide-specific assay.
`
`34.
`
`(Previously Presented) The solid composition of claim 31, wherein the composition
`
`maintains total impurities of less than 3% and/or a sincalide level of at least 90% after 15 months
`
`of storage at 25°C, 60% relative humidity when tested by a sincalide-specific assay.
`
`35.
`
`(Previously Presented) The solid composition of claim 1, further comprising
`
`(a) at least one stabilizer,
`
`(b) at least one bulking agent/tonicity adjuster,
`
`( c) at least one chelator, or
`
`(d) any combination of (a)-(c), and
`
`8
`
`8
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`wherein the composition does not contain a buffer having a pKa within one unit of the
`
`pH.
`
`36.
`
`(Previously Presented) The solid composition of claim 35, wherein the composition
`
`(a) is a lyophilized powder and/or
`
`(b) maintains total impurities of less than 5% and/or a sincalide level of at least 90% after
`
`15 months of storage at 25°C, 60% relative humidity when tested by a sincalide-specific assay.
`
`37.
`
`(Previously Presented) The solid composition of claim 36, wherein the composition does
`
`not contain either or both polysorbate 20 and polysorbate 80.
`
`38.
`
`(Previously Presented) The solid composition of claim 36, wherein
`
`(a) the at least one stabilizer is selected from the group consisting of pentetic acid,
`
`arginine hydrochloride, L-methionine, L-lysine hydrochloride, sodium metabisulfite, and
`
`combination thereof,
`
`(b) the at least one bulking agent/tonicity adjuster is mannitol, and
`
`( c) the at least one chelator is selected from edetic acid and/or pentetic acid.
`
`39.
`
`(Previously Presented) The solid composition of claim 38, wherein the composition does
`
`not contain either or both polysorbate 20 and polysorbate 80.
`
`40.
`
`(Previously Presented) The solid composition of claim 1, wherein the composition further
`
`compnses
`
`(a) at least one stabilizer,
`
`(b) at least one bulking agent/tonicity adjuster,
`
`( c) at least one chelator, or
`
`(d) any combination of (a)-(c),
`
`9
`
`9
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`wherein the composition does not contain a buffer having a pKa within one unit of the
`
`pH, and
`
`wherein the composition does not contain polysorbate 20, and
`
`wherein the composition does not contain polysorbate 80.
`
`41.
`
`(Previously Presented) The solid composition of claim 40, wherein the composition
`
`(a) is a lyophilized powder and/or
`
`(b) maintains total impurities of less than 5% and/or a sincalide level of at least 90% after
`
`15 months of storage at 25°C, 60% relative humidity when tested by a sincalide-specific assay.
`
`42.
`
`(Previously Presented) The solid composition of claim 41, wherein
`
`(a) the at least one stabilizer is selected from the group consisting of pentetic acid,
`
`arginine hydrochloride, L-methionine, L-lysine hydrochloride, sodium metabisulfite, and
`
`combination thereof,
`
`(b) the at least one bulking agent/tonicity adjuster is mannitol, and
`
`( c) the at least one chelator is selected from edetic acid and/or pentetic acid.
`
`43.
`
`(Previously Presented) The solid composition of claim 4, wherein the composition further
`
`compnses
`
`(a) at least one stabilizer,
`
`(b) at least one bulking agent/tonicity adjuster,
`
`( c) at least one chelator, or
`
`(d) any combination of (a)-(c), and
`
`wherein the composition does not contain a buffer having a pKa within one unit of the
`
`pH.
`
`44.
`
`(Previously Presented) The solid composition of claim 43, wherein the composition
`
`(a) is a lyophilized powder and/or
`
`(b) maintains total impurities of less than 5% and/or a sincalide level of at least 90% after
`
`10
`
`10
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`15 months of storage at 25°C, 60% relative humidity when tested by a sincalide-specific assay.
`
`45.
`
`(Previously Presented) The solid composition of claim 44, wherein
`
`(a) the at least one stabilizer is selected from the group consisting of pentetic acid,
`
`arginine hydrochloride, L-methionine, L-lysine hydrochloride, sodium metabisulfite, and
`
`combination thereof,
`
`(b) the at least one bulking agent/tonicity adjuster is mannitol, and
`
`( c) the at least one chelator is selected from edetic acid and/or pentetic acid.
`
`11
`
`11
`
`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`REMARKS
`
`This Amendment and the following remarks are intended to fully respond to the non-final
`
`Office Action dated November 19, 2018 hereinafter "Office Action."
`
`Amendment to the Specification
`
`The specification is amended herein to delete recitation of "glycine and other amino
`
`acids/amino acid salts" from a list of exemplary surfactants. No new matter is added by way of
`
`this amendment, and entry is respectfully requested.
`
`Status of the claims
`
`In this Amendment, claims 1-6, and 13-14 (both withdrawn) are amended.
`
`Applicant submits that claim amendments are supported throughout the specification, and
`
`in the claims as originally filed, and do not introduce new matter. See, e.g., claim 2 as originally
`filed (now cancelled); see also Specification, at ,i [0043].
`
`The amendments are made herein without acquiescing to any allegations set forth in the
`
`Office Action, and without prejudice or disclaimer of Applicant's rights to pursue cancelled
`
`subject matter in a continuing application. Applicant expressly reserves the right to pursue the
`
`subject matter of any cancelled or amended claims, without prejudice, in one or more divisional,
`
`continuation, or continuation-in-part applications.
`
`Interview Summary
`
`Applicant respectfully thanks Examiners Al-Awadi and Wax for the courtesies extended
`
`to its representative, Rita Wu, during a telephonic interview held on January 29, 2019. In the
`
`interview, the cited reference of Metcalfe (US 20100047175) particularly at paragraph
`
`[0038]-[0039], the purpose of a buffer, and the novelty and non-obviousness of formulations
`
`lacking a buffer were discussed. See, Interview Summary issued February 4, 2019 (hereinafter
`
`"Interview Summary").
`
`12
`
`12
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`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`35 u.s.c. § 102
`Claims 1, 3-8, and 10 stand rejected under 35 U.S.C. § 102(a)(l) as allegedly anticipated
`
`by Metcalfe et al. (US 20100047175) (hereinafter Metcalfe et al.). Previous claims 2, 9, and
`
`31-45 are considered novel over Metcalfe et al.
`
`Without acquiescing to the allegation, solely for the purposes of expediting prosecution,
`
`and without prejudice or disclaimer of Applicant's rights to pursue any cancelled subject matter,
`
`independent claim 1 is amended herein to recite composition comprises a pH from 6 to 8 when
`
`reconstituted in a pharmaceutically acceptable diluent and that the composition does not contain
`
`a phosphate buffer. See, e.g., previous claim 2 (now cancelled); see also Interview Summary, at
`
`p. 1 (stating "[t]he Examiner suggested that incorporating the limitation where the formulation
`
`does not contain any phosphate buffer would overcome the 102.") Applicant respectfully
`
`submits that this amendment renders the rejection under 35 U.S.C. § 102 no longer applicable.
`
`35 u.s.c. § 103
`
`Claims 1, 2, 9 and 31-45 are rejected under 35 U.S.C. § 103 as allegedly unpatentable
`
`over Metcalfe et al. (US 20100047175) (hereinafter Metcalfe et al.). Specifically, the Office
`
`Action at page 7 states:
`
`[I]t would have [been] obvious to one of ordinary skill in the art before the effective
`filing date to have selected various combinations of the various disclosed ingredients in
`Metcalfe such as formulations that have buffers that do not include dibasic potassium
`phosphate, and comprise pentetic acid, arginine hydrochloride, methionine, lysine
`hydrochloride, sodium metabisulfite, and mannitol to arrive at compositions yielding no
`more than one would expect from such an arrangement which is a stable sincalide
`formulation.
`
`Applicant respectfully disagrees and submits that such conclusory statement is unsupported by
`
`any rational underpinning.
`
`As the Federal Circuit recently stated, "to have a reasonable expectation of success, one
`
`must be motivated to do more than merely vary all parameters or try each of numerous
`
`possible choices until one possibly arrived at a successful result." See, In re Stepan Co., 868
`
`F.3d 1342, 1346 (2017) (emphasis added) (finding the claims at issue therein not obvious over
`
`the cited art since the Office failed to articulate "why a person of ordinary skill in the art would
`
`13
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`13
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`

`

`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`have had a reasonable expectation of success."). Applicant respectfully submits that similar to
`
`the Stepan case, the record lacks any articulation as to why a skilled artisan would be motivated
`
`to try a formulation lacking a phosphate buffer with any reasonable expectation of success.
`
`Specifically, Applicant respectfully submits that a primafacie case of obviousness has not been
`
`established for the instant claims since the Office failed to show how, (A) when read in light of
`
`the historical instability of sincalide, Metcalfe et al. provides (B) motivation to a skilled artisan
`
`to formulate a sincalide composition without a phosphate buffer.
`
`A Instability of historical sincalide formulations
`
`As an initial matter, Applicant respectfully directs attention to Metcalfe et al. at
`
`paragraphs [0003]-[0005]. As described, the two ingredient KINEVAC® formulation
`
`introduced in 1976 "suffers from potency variability" and "there is a need for sincalide
`
`formulations having improved and consistent potency." Id Metcalfe et al. attempts to satisfy
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`this need by testing the effects of not only a buffering agent and pH on sincalide formulations,
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`see Metcalfe et al. at Example 1, but also chelators (example 2), surfactants (example 3),
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`antioxidants (example 4), and bulking agents/tonicity adjusters (example 5). Id It is against this
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`backdrop, and the continued instability of sincalide formulations, that the teachings of Metcalfe
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`et al. should be evaluated. See, e.g., Specification, at paragraph [0006] (stating "the current
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`formulation ofKINEVAC® [comprising 170 mg mannitol as a bulking agent/tonicity adjuster;
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`30 mg of lysine, 15 mg of arginine, and 4 mg of methionine as stabilizers; 2 mg of pentetic acid
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`as a chelator; 0.04 mg of sodium metabisulfite as a stabilizer/antioxidant; 0.005 mg of
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`polysorbate (Tween) 20 as a surfactant/solubilizer; 9 mg potassium phosphate dibasic as a
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`buffer; and hydrochloric acid and/or sodium hydroxide to adjust the pH to 6.0 to 8.0] appears to
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`have issues with stability, as in January 2015, FDA approved a request to have KINEVAC's®
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`shelf-life reduced from 24 months to 15 months when stored at 25°C").
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`As reviewed below, Applicant respectfully submits that when reviewed against the
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`historical instability of sincalide formulations, it becomes clear that the instant rejection under 35
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`U.S.C. § 103 is supported only with the impermissible aid of hindsight analysis. Specifically,
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`Applicant respectfully notes that the record lacks any evidence a skilled artisan would be
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`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
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`motivated to modify Metcalfe et al. as proposed (e.g., to try "formulations that have buffers that
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`do not include [a phosphate buffer]") and/or have any reasonable expectation of success in doing
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`SO.
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`B. The record lacks any evidence a skilled artisan would be motivated to modify
`Metcalfe et al. as proposed
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`During the telephonic interview, it became apparent that the Office is alleging that the
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`recitation of different buffers at paragraphs [0009] and [0038] of Metcalfe et al. suggests a genus
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`of buffers useful in sincalide formulations, and that one of ordinary skill would not only choose
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`one of those buffers in formulating their sincalide composition, but also use their choice in lieu
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`of a phosphate buffer. Applicant respectfully disagrees.
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`When determining obviousness of a species in view of the prior art genus, MPEP §
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`2144.08 specifically explains that
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`Office personnel should make explicit findings on the similarities and
`differences between the closest disclosed prior art species of subgenus of
`record and the claimed species or subgenus including findings relating to
`similarity of structure, properties and utilities ... and whether it would
`have been obvious to one of ordinary skill ... to select the claimed species
`or subgenus from the disclosed prior art genus.
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`In the present case, Applicant respectfully notes that the record is absent any
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`consideration of (i) the size of the allegedly obvious genus, (ii) the express teachings of Metcalfe
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`et al. as a whole, and/or (iii) teachings ( or lack thereof) of similar properties or uses. Applicant
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`respectfully addresses these considerations in tum.
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`i.
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`Size of the allegedly obvious genus
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`Applicant respectfully submits that the size of the genus of buffers allegedly disclosed by
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`Metcalfe et al. does not support aprimafacie case of obviousness. MPEP § 2144.08
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`(II)(A)( 4)(A) (citing In re Ruschig 343 F.2d 965,874 (CCPA 1965), which states that "rejection
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`of claimed compound in light of prior art genus ... is not appropriate where the prior art does
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`not disclose a small recognizable class of compounds with common properties.") Paragraph
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`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`[0038] of Metcalfe et al. states "[b ]uffering agents are employed to stabilize the pH of sincalide
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`formulations of the invention, and consequently reduce the risk of chemical stability at extreme
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`pH values." In enumerating exemplary buffering agents, Metcalfe et al. describes over 40
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`classes of buffers and specific buffers. Therefore, Metcalfe et al. provides an innumerable
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`genus of buffers that may stabilize the pH of a sincalide formulation, each of which has a
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`buffering capacity at a different pH range. Applicant respectfully submits that such a size cannot
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`be considered a small recognizable class of compounds that would motivate a skilled artisan to
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`remove a phosphate buffer as taught by Metcalfe et al. in its formulation of a stable sincalide
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`composition. Even assuming, arguendo, that paragraph [0009] of Metcalfe et al. provides a
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`smaller genus of buffers, see, e.g., Office Action, at p. 5, Applicant respectfully disagrees that
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`such teaching in Metcalfe et al., when read in light of the state of the art as described herein and
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`the express teaching Metcalfe et al. as whole, provides any more motivation or reasonable
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`expectation of success than paragraph [0038], particularly since, as described below, there is no
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`express teaching in Metcalfe et al. or on record describing any of these buffers as having the
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`same properties as a phosphate buffer.
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`ii.
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`Express teachings
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`Applicant respectfully submits that the express teachings of Metcalfe et al. also do not
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`provide a skilled artisan any motivation to modify it as proposed.
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`As an initial matter, Applicant respectfully submits that nowhere in Metcalfe et al. is
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`there a teaching or suggestion of a sincalide formulation lacking a phosphate buffer, much less
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`wherein the sincalide formulation comprises a pH of about 6 to about 8.
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`However, the Office sates at pages 5 and 7:
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`Metcalfe et al. discloses that the formulations of the invention preferably have a pH
`between 6 and 8. Suitable buffers include phosphate, citrate, sulfosalicylate, borate,
`acetate and amino acid buffers.
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`[I]t would have been obvious to one of ordinary skill in the art to have selected various
`combinations of the various disclosed ingredients in Metcalfe such as formulations that
`have buffers that do not include dibasic potassium phosphate ... to arrive at compositions
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`U.S. Patent Application Serial No. 15/958,854
`Amendment dated February 19, 2019
`Reply to Office Action of November 19, 2018
`
`yielding no more than one would expect from such an arrangement which is a stable
`sincalide formulation. Id. See also, Metcalfe et al, at ,i [0009].
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`Additionally, during the telephonic interview, the Examiner kindly directed attention to
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`paragraph [0038] of Metcalfe et al. as providing a skilled artisan with the motivation to use any
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`one of those recited buffers in lieu of a phosphate buffer. Applicant respectfully disagrees.
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`To the contrary, Applicant respectfully submits that Metcalfe et al. as a whole teaches the
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`opposite, i.e., that use of phosphate buffer results in the stability of a sincalide formulation at a
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`physiologic pH range, e.g., 6-8. Specifically, Applicant respectfully notes that Metcalfe et al.
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`states the following:
`
`•
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`"[b ]uffering agents are employed . . . to reduce the risk of chemical stability at
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`extreme pH values," at paragraphs [0037]-[0039]
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`•
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`"[a]s described in Example 1 below, a sincalide formulation of the invention proved
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`to be stable over a pH range of 5.5-9.1," at paragraph [0039]
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`•
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`"[a]t pH values< 5.0, sincalide degradation was evident." Example 1, paragraphs
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`[0073]-[0075].
`
`•
`
`"Based on the results shown in Table 3, phosphate was selected as the buffering
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`agent of choice due to a lack of interaction with sincalide and an ideal buffering
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`capacity in the physiological range. Subsequently, experiments using phosphate in
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`the formulation shown in Table 4 over the stable pH range established above were
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`performed ... [S]olutions ... containing the following components ... were
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`prepared ... dibasic potassium phosphate," at paragraph [0075].
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`In summary, Applicant respectfully submits that Metcalfe et al. teaches phosphate buffer as the
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`buffer of choice to reduce the risk of chemical stability for sincalide formations having a pH in
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`the physiological range, e.g., a pH of about 6 to about 8, because of its (1) lack of interaction
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`with sincalide and (2) ideal buffering capacity in the physiological range. Absent evidence on
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`the record that a sub