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`SCORE Placeholder Sheet for IFW Content
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`Application Number: 16248460
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`Document Date: 01/15/2019
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`record were created from the original documents that are stored in SCORE.
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`Form Revision Date: August 26, 2013
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`Doc Code: TRACK1.REQ
`Document Description: TrackOne Request
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`PTO/AIA/424 (04-14)
`
`CERTIFICATION AND REQUEST FOR PRIORITIZED EXAMINATION
`UNDER 37 CFR 1.102(e) (Page 1 of 1)
`
`John Maloney
`
`I Nonprovisional Application Number (if I
`
`known):
`
`STABLE, HIGHLY PURE L-CYSTEINE COMPOSITIONS FOR INJECTION AND METHODS OF USE
`
`First Named
`Inventor:
`Title of
`Invention:
`
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTS PRIORITIZED EXAMINATION FOR
`THE ABOVE-IDENTIFIED APPLICATION.
`
`1. The processing fee set forth in 37 CFR 1.17(i)(1) and the prioritized examination fee set forth in
`37 CFR 1.17(c) have been filed with the request. The publication fee requirement is met
`because that fee, set forth in 37 CFR 1.18(d), is currently $0. The basic filing fee, search fee,
`and examination fee are filed with the request or have been already been paid. I understand
`that any required excess claims fees or application size fee must be paid for the application.
`
`2.
`
`I understand that the application may not contain, or be amended to contain, more than four
`independent claims, more than thirty total claims, or any multiple dependent claims, and that
`any request for an extension of time will cause an outstanding Track I request to be dismissed.
`
`3. The applicable box is checked below:
`
`I.
`
`[?] Original Application (Track One) - Prioritized Examination under§ 1.102(e)(1)
`
`i.
`
`(a) The application is an original nonprovisional utility application filed under 35 U.S.C. 111 (a).
`This certification and request is being filed with the utility application via EFS-Web.
`---OR---
`(b) The application is an original nonprovisional plant application filed under 35 U.S.C. 111 (a).
`This certification and request is being filed with the plant application in paper.
`
`ii. An executed inventor's oath or declaration under 37 CFR 1.63 or 37 CFR 1.64 for each
`inventor, or the application data sheet meeting the conditions specified in 37 CFR 1.53(f)(3)(i) is
`filed with the application.
`II. D Request for Continued Examination - Prioritized Examination under§ 1.102(e)(2)
`i. A request for continued examination has been filed with, or prior to, this form.
`ii.
`If the application is a utility application, this certification and request is being filed via EFS-Web.
`iii. The application is an original non provisional utility application filed under 35 U.S.C. 111 (a), or is
`a national stage entry under 35 U.S.C. 371.
`iv. This certification and request is being filed prior to the mailing of a first Office action responsive
`to the request for continued examination.
`v. No prior request for continued examination has been granted prioritized examination status
`under 37 CFR 1.102(e)(2).
`
`Sionatur/bryan I. Skelton/
`~p~~~voed) Bryan L. Skelton
`
`DateJanuary 15, 2019
`50893
`
`Practitioner
`Reoistration Number
`
`Note: This form must be signed in accordance with 37 CFR 1.33. See 37 CFR 1.4(d) for signature requirements and certifications.
`Submit multiole forms if more than one sianature is reauired. *
`
`~ *Total of 1
`
`forms are submitted.
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`ST ABLE, HIGHLY PURE L-CYSTEINE COMPOSITIONS FOR INJECTION AND
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`Atty. Ref. No. 066859/509450
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`METHODS OF USE
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`TECHNICAL FIELD
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`5
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`The subject matter described herein relates generally to compositions for parenteral
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`administration comprising L-cysteine that are stable and have desirable safety attributes
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`for extended periods of time.
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`BACKGROUND
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`L-cysteine is a sulfur-containing amino acid that can be synthesized de nova
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`10
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`from methionine and serine in adult humans. L-cysteine performs a variety of
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`metabolic functions. For example, L-cysteine is involved in growth and protein
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`synthesis and it is a precursor for glutathione, an important intracellular antioxidant.
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`L-cysteine is generally classified as a non-essential amino acid or "semi(cid:173)
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`essential" amino acid because it can be synthesized in small amounts by the human
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`body. However, some adults can still benefit from L-cysteine supplementation.
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`Further, L-cysteine has been classified as conditionally essential in some cases. For
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`example, L-cysteine can be conditionally essential in preterm infants due to
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`biochemical immaturity of the enzyme cystathionase that is involved in L-cysteine
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`synthesis.
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`Thus, there are a number of circumstances in which L-cysteine
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`20
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`supplementation can be desirable.
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`The subject matter described herein addresses the shortcomings of the art by
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`providing L-cysteine compositions that facilitate the desired supplementation but
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`with an exceptional safety, purity and stability profile.
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`BRIEF SUMMARY
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`25
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`In certain aspects, the subject matter described herein is directed to a safe, stable L(cid:173)
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`cysteine composition for parenteral administration, comprising:
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`L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in
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`an amount from about IO mg/mL to about I 00 mg/mL;
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`Aluminum (Al) in an amount from about 1.0 part per billion (ppb) to about 250
`
`ppb;
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`5
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`L-cystine in an amount from about 0.001 wt% to about 2.0 wt% relative to L(cid:173)
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`cysteine;
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`pyruvic acid in an amount from about 0.001 wt% to about 2.0 wt% relative to L(cid:173)
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`cysteine;
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`a pharmaceutically acceptable carrier, comprising water;
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`10
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`headspace 02 that is from about 0.5% to 4.0% from the time of manufacture to
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`about I month from manufacture when stored at room temperature;
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`dissolved oxygen present in the carrier in an amount from about 0.1 parts per
`
`million (ppm) to about 5 ppm from the time of manufacture to about I month from
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`manufacture when stored at room temperature,
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`15
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`wherein the composition is enclosed in a single-use container having a volume of
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`from about IO mL to about I 00 mL.
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`In certain aspects, the subject matter described herein is directed to a safe, stable L(cid:173)
`
`cysteine composition for parenteral administration, comprising:
`
`L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in
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`20
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`an amount from about 10 mg/mL to about 100 mg/mL;
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`Aluminum (Al) in an amount from about 1.0 parts per billion (ppb) to about 250
`
`ppb;
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`L-cystine in an amount from about 0.001 wt% to about 2.0 wt% relative to L(cid:173)
`
`cysteine;
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`25
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`pyruvic acid in an amount from about 0.001 wt% to about 2.0 wt% relative to L-
`
`cysteine;
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`a pharmaceutically acceptable carrier, comprising water;
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`headspace 02 that is from about 0.5% to 4.0% from the time of manufacture to
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`about 1 month from manufacture when stored at room temperature;
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`dissolved oxygen present in the carrier in an amount from about 0.1 parts per
`
`million (ppm) to about 5 ppm from the time of manufacture to about I month from
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`manufacture when stored at room temperature,
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`optionally one or more metals selected from the group consisting of Lead from
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`5
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`about 1.0 ppb to about 10 ppb, Nickel from about 5 ppb to about 40 ppb, Arsenic from
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`about 0.1 ppb to 10 ppb, and Mercury from about 0.2 ppb to about 5.0 ppb;
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`wherein the composition is enclosed in a single-use container having a volume of
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`from about IO mL to about I 00 mL.
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`In certain aspects, the subject matter described herein is directed to a safe, stable
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`composition from about 100 mL to about 1000 mL for administration via a parenteral
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`infusion within about 24 to about 48 hours of admixture, comprising a mixture of a
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`composition of L-Cysteine described herein; and an amino acid composition that is
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`essentially free of L-Cysteine comprising one or more amino acids selected from the group
`
`consisting of: leucine, isoleucine, lysine, valine, phenylalanine, histidine, threonine,
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`15
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`methionine, tryptophan, alanine, arginine, glycine, praline, serine, and tyrosine.
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`In certain aspects, the subject matter described herein is directed to a method of
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`reducing Aluminum administration from a total parenteral nutrition regimen comprising
`
`L-cysteine, the method comprising, mixing a composition comprising L-cysteine or a
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`pharmaceutically acceptable salt thereof and/or hydrate thereof comprising:
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`20
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`Aluminum in an amount from about 1.0 parts per billion (ppb) to about 250 ppb;
`
`L-cystine in an amount from about 0.001 wt% to about 2.0 wt% relative to L(cid:173)
`
`cysteine; and
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`pyruvic acid in an amount from about 0.001 wt% to about 2.0 wt% relative to L(cid:173)
`
`cysteine;
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`25
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`with a composition comprising one or more amino acids selected from the group
`
`consisting of: leucine, isoleucine, lysine, valine, phenylalanine, histidine, threonine,
`
`methionine, tryptophan, alanine, arginine, glycine, praline, serine, and tyrosine; and
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`a pharmaceutically acceptable carrier, comprising water,
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`to form a composition for infusion having a volume of about 100 mL to about 1000 mL,
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`3
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`wherein the Aluminum provided in said parenteral nutrition regimen is from about 1-2 to
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`about 4-5 micrograms/kg/day.
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`In certain aspects, the subject matter described herein is directed to methods of
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`treating a subject having an adverse health condition that is responsive to L-cysteine
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`administration, comprising:
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`diluting a stable L-cysteine composition as described herein with an intravenous
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`fluid to prepare a diluted L-cysteine composition for infusion; and
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`infusing the diluted L-cysteine composition for infusion to a subject to provide a
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`therapeutically effective dose of L-cysteine or a pharmaceutically acceptable salt thereof
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`10
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`and/or hydrate thereof to the subject in a therapeutically effective dosing regimen.
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`In certain aspects, the subject matter described herein are directed to methods of
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`administering L-Cysteine together with a composition for parenteral nutrition, comprising:
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`diluting a stable L-cysteine composition for injection as described herein with a
`
`parenteral nutrition composition to form a mixture; and
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`15
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`parenterally administering the mixture to a subject in need thereof in a
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`therapeutically and/or nutritionally effective dose. In one aspect, the subject is a preterm
`
`infant or newborn to about 1 month of age. Some of these subjects may weigh from about
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`0.5 kilos to about 2.0 kilos. In another aspect, the subject is a pediatric patient that is of
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`about 1 month to six months of age. Some of these subjects may weigh from about 0.2
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`20
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`kilos to about 20 kilos. In another aspect, the subject is an adult requiring parenteral
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`nutrition.
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`These and other aspects are more fully described herein.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`Figure 1 depicts the overall trend of the results from the experiments that
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`25
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`demonstrate the effectiveness of the Head Space Reduction (HSR) cycle in attaining
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`reduced and consistent dissolved oxygen (DO) levels in the finished drug product. The
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`results showed a trend with an increase in dissolved oxygen level from 0.36 parts per
`
`million (ppm) recorded during compounding, to an average of 5.12 ppm measured after
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`filling, a further increase to an average of 9.92 ppm while loading the Lyophilizer, and
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`finally a reduction of dissolved oxygen to an average of 0.50 ppm after headspace
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`reduction. This demonstrates the specific phase of manufacturing at which and to the
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`specific level that oxygen needs to be controlled in the product.
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`Figure 2 depicts the overall trend of the results from the experiments that
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`5
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`demonstrate the effectiveness of the Head Space Reduction (HSR) cycle in attaining
`
`reduced and consistent dissolved oxygen (DO) levels in the finished drug product. The
`
`results showed a trend with an increase in dissolved oxygen level from 0.36 parts per
`
`million (ppm) recorded during compounding, to an average of 5.12 ppm measured after
`
`filling, a further increase to an average of 9.92 ppm while loading the Lyophilizer, and
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`10
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`finally a reduction of dissolved oxygen to an average of 0.50 ppm after headspace
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`reduction.
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`Figure 3 depicts a process filler set up to fill and reduce head space oxygen.
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`Figure 4 shows data for the process of Example 4. The plot shows comparison of
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`oxygen headspace control between the lyophilizer chamber headspace control method
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`15
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`versus the high-speed filler vacuum stoppering system. The time zero oxygen headspace
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`results for the batch PROT-000213 are shown in comparison to the previously
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`manufactured lots. Results shown were measured at the time of manufacturing on samples
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`of vials from the batches.
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`Figure 5 depicts the data measured for dissolved oxygen levels in the process of
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`20
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`Example 4.
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`DETAILED DESCRIPTION
`
`The presently disclosed subject matter will now be described more fully hereinafter.
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`However, many modifications and other embodiments of the presently disclosed subject
`
`matter set forth herein will come to mind to one skilled in the art to which the presently
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`25
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`disclosed subject matter pertains having the benefit of the teachings presented in the
`
`foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject
`
`matter is not to be limited to the specific embodiments disclosed and that modifications
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`and other embodiments are intended to be included within the scope of the appended
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`claims.
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`In other words, the subject matter described herein covers all alternatives,
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`modifications, and equivalents that are within the ordinary skill in the art. In the event that
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`one or more of the incorporated literature, patents, and similar materials differs from or
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`5
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`contradicts this application, including but not limited to defined terms, term usage,
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`described techniques, or the like, this application controls. Unless otherwise defined, all
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`technical and scientific terms used herein are intended to have the same meaning as
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`commonly understood by one of ordinary skill in this field. All publications, patent
`
`applications, patents, and other references mentioned herein are incorporated by reference
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`10
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`in their entirety.
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`Advantageously, it has been found that the desirable attributes of L-cysteine
`
`compositions for infusion can be obtained without the characteristic impurity profile that
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`is known in the art. Such impurity profile makes the product less safe to be used by
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`patients, in particular, preterm and term infants and pediatric patients of 1 month to 1 year
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`15
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`as well as critically ill adults. Specifically, the art formulations fail to address the issues
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`related to the amounts of Aluminum and cystine, among other impurities, that can be
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`routinely present and co-administered with L-cysteine. It has now been found that L(cid:173)
`
`cysteine compositions for injection can be prepared using the methods described herein
`
`whereby the compositions unexpectedly comprise exceedingly low levels of Aluminum
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`20
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`and other undesirable impurities, such as cystine, pyruvic acid, certain heavy metals and
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`certain ions. As a result, the present compositions and methods of using said compositions
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`are safer to the intended subject compared to the currently available compositions and
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`methods. Further, the product is also rendered more stable by virtue of lower levels of
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`cystine generated by the manufacturing processes described herein.
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`25
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`As described herein, without being bound to theory, it has been found that the
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`problems of safety, purity and stability are results not simply or directly from the level of
`
`Aluminum, but are also intertwined with dissolved oxygen levels in the composition and
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`oxygen in the headspace as well as certain heavy metals and certain ions that may leach or
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`be extracted out of the container closure.
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`An L-Cysteine for injection product was prepared with the aim to provide a product
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`that would be acceptable for administration to infants, pediatric and adult patients. High
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`quality Schott glass vials and stoppers were used. See Example 2. It was however found
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`that glass containers contribute more significantly than expected to the Aluminum content
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`5
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`of L-cysteine compositions stored therein to the point where the product did not meet the
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`specifications for certain components. Products having such Aluminum levels would
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`likely be deemed unsafe by the FDA. As such, efforts were focused on identifying the
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`sources of Aluminum in the product and attempts to minimize it in the product. These
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`efforts led to the unexpected discovery that simply removing a source of Aluminum by
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`10
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`replacing glass with plastic did not result in a product having the desired properties.
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`Additional efforts to identify the root cause for the product failure led to the finding
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`that the product likely failed because oxygen entered the plastic container and into the
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`product at a rate higher than previously expected or predicted. For example, the plastic
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`container product failed in some cases in less than 1-2 months. See Example 3. This finding
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`was also unexpected. Increased oxygen levels in the product led to unacceptable levels of
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`oxidation products, such as cystine, which precipitated and caused particulates in the
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`product. Particulates are dangerous in injectable compositions and create a safety concern,
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`in addition to the stability issue to the product.
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`However, the precipitation may have been exacerbated by reduction in Aluminum
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`20
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`smce Aluminum in solution may have a stabilizing effect. Consequently, removing
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`Aluminum may have the unintended consequence of increased precipitation and product
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`failure in the presence of even small amounts of oxygen in the container. This was
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`unexpected.
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`Additionally, controlling heat in the process including during the compounding
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`25
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`and/or sterilization activities, unexpectedly was found to be beneficial for preparing stable
`
`L-Cysteine compositions described herein. This was surprising because L-Cysteine has
`
`been used in parenteral products as an excipient where the product is subjected to terminal
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`sterilization which exposes the product to high temperatures such as 120 °C.
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`Some subjects that would be rece1vmg L-Cysteine supplementation are, as
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`discussed elsewhere herein, pre-term neonates or full-term infants that are underweight, or
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`infants that may be full term and are not underweight but are still candidates for treatment,
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`in many cases for longer term treatment. For example, some of these subjects may be
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`5
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`treated with L-Cysteine for several days or several weeks, even several months. In these
`
`cases, it is imperative that the subjects are not exposed to potentially toxic or undesirable
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`levels of some anions and heavy metals that may be present in drug products. Examples of
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`such heavy metals include but not limited to Lead, Nickel, Arsenic and Mercury. Examples
`
`of anions that should be monitored include but not limited to iodide, and fluoride. Many
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`10
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`of these are introduced into drug products through manufacturing processes, container
`
`closure systems, or the drug substance and the excipients. The levels of the heavy metals
`
`and anions may not be a concern with many drug products because the patient population
`
`exposed to the drug may be not as vulnerable as in the case of L-Cysteine, or the dosing of
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`such drug products may be very limited, i.e., for one or a few doses. For the reasons noted
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`15
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`above, it is imperative that L-Cysteine drug product, its administration, its manufacture,
`
`and its container closure system are carefully evaluated for the levels of heavy metals and
`
`selected anions. The state of the art is lacking in providing any specific guidance on the
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`need for this evaluation, the specific heavy metals and anions on which to focus, and how
`
`to achieve control over the levels.
`
`The L-Cysteine compositions, methods of
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`20
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`administration and manufacture, selection of container closure system and the excipients
`
`and the drug substance as described herein fill that need.
`
`Thus, in summary, as described herein, reducing aluminum drastically to extremely
`
`low levels in the product, reducing oxygen to very low levels in the process and in the
`
`composition, and/or reducing or eliminating heat in the process, and in consideration of
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`25
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`data showing selection of the appropriate container, stopper, drug substance, and
`
`excipients, individually or in combination(s),
`
`resulted in achieving
`
`a safe, stable
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`composition of L-Cysteine injection that could be administered safely even to very delicate
`
`pediatric subjects such as pre-term neonatal subjects that are as young as a day and may
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`weigh as low as 0.5 kilos, for a few days to several weeks.
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`L-cysteine for injection is a marketed product used as a component of a nutritional
`
`supplement regimen referred to as total parenteral nutrition (TPN). The Aluminum content
`
`in known L-cysteine compositions for injection is higher than desired. Moreover, when
`
`the L-cysteine composition is combined with certain amino acids prior to administration,
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`5
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`the amino acids contribute some amount of Aluminum, and Aluminum levels can further
`
`increase. TPN admixtures constitute several other components (in addition to amino acid
`
`mixtures) such as electrolytes (such as Potassium Phosphate, Calcium gluconate, and
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`sodium acetate). These electrolytes may also contribute to high Aluminum levels in TPN
`
`admixtures (Smith et al., Am. J. Health Syst. Pharm., vol. 64, April, 1, 2007, pp. 730-739).
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`This is of particular concern since administration of the L-cysteine is often to infants (some
`
`of them pre-term) for nutritional support. A focus of the subject matter described herein is
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`in minimizing the Aluminum levels coming from L-Cysteine compositions so that when
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`admixed with other ingredients of TPN admixtures, the overall Aluminum levels could be
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`reduced while minimizing introduction of undesirable materials such as heavy metals,
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`anions, and particulates. All of these components are present in amounts that are below
`
`levels determined to be safe.
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`L-cysteine (2-Amino-3-sulfhydrylpropanoic acid) is a sulfur-containing amino
`
`acid having a structure according to Formula I:
`
`(I)
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`20
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`L-cysteine performs a variety of metabolic functions. For example, L-cysteine is a
`
`precursor for antioxidants, such as glutathione and taurine, that support oxidative defense
`
`and a healthy immune system. L-cysteine can also play a role in the synthesis of essential
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`fatty acids and facilitate production of cell membranes and protective covers of nerve
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`endings. Additionally, L-cysteine can be an important precursor for many proteins, such
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`as structural proteins in connective tissue. Thus, the depletion or absence of cystathionase
`
`activity in premature fetuses and newborns to synthesize L-cysteine de nova has led to the
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`categorization of L-cysteine as a conditionally essential amino acid. Additionally,
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`administration of L-cysteine can be valuable to treat a number of conditions in subjects,
`
`whether or not the subject is a premature infant or neonate.
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`Known pharmaceutical compositions that contain L-cysteine can typically contain
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`5
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`undesirable levels of certain components. Cystine is an oxidation product of L-cysteine.
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`Like L-cysteine, cystine can be synthesized in the liver. Further, both L-cysteine and
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`cystine can be present as amino acid residues in proteins. However, because cystine is an
`
`oxidation product of L-cysteine, it is possible that the amount of cystine can increase over
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`time. Thus, it may be desirable to maintain the amount of cystine within predetermined
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`levels over time. For all practical purposes, cystine and L-Cystine are used interchangeably
`
`herein. Pyruvic acid is another undesirable compound that can be found in L-cysteine
`
`compositions known in the art. It is possible that the amount of pyruvic acid in these
`
`compositions can increase over time. Thus, it may be desirable to maintain the amount of
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`pyruvic acid within predetermined levels over time.
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`Perhaps of most concern is the level of Aluminum in known L-cysteine
`
`compositions. Aluminum contamination and associated Aluminum toxicity can lead to a
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`number of adverse conditions such as metabolic bone disease, neurodevelopmental delay,
`
`cholestasis, osteoporosis, growth failure, dementia, and the like. It is desirable to allow no
`
`more than 4-5 mcg/kg/day of Aluminum to avoid toxicity. It is preferable to keep the dose
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`on the conservative side as much as possible, i.e., at 4 mcg/kg/day to avoid accidental
`
`overdosing in case Aluminum from some other reason (unanticipated or unknown source
`
`or due to human error) is introduced. Up to now, known L-cysteine compositions contain
`
`up to 5000 ppb Aluminum. Even levels of 900 ppb are known in currently available
`
`products. In stark contrast, described herein are compositions that provide a therapeutically
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`effective amount of L-cysteine, while containing less than 250 ppb Aluminum, including,
`
`in certain embodiments, less than 200 ppb, or less than 175 ppb, or less than 150 ppb, or
`
`less than 125 ppb, or less than 120 ppb, or less than 100 ppb, or less than 80 ppb, or less
`
`than 75 ppb, or less than 60 ppb, or less than 50 ppb, or less than 40 ppb, or less than 30
`
`ppb, or less than 20 ppb, or less thanlO ppb, or less than 5 ppb, or less than 1.0 ppb. Thus,
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`what has now been achieved is an unexpected and substantial reduction in Aluminum
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`content of an L-Cysteine composition that permits exposure to less than or equal to 4-5
`
`micrograms per kilogram per day (µg/kg/d) to avoid or minimize Aluminum toxicity while
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`still providing therapeutically effective L-cysteine in a stable composition. In some aspects,
`
`the compositions described herein permit an Aluminum dose of as
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`low as 0.6
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`5
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`micrograms/kg/d, improving significantly the safety of the L-Cysteine product and its
`
`administration.
`
`High risk patient populations for Aluminum toxicity in the context of parenteral
`
`nutrition include the following: Renal Insufficiency and Infants: Renal elimination is a
`
`major source of Aluminum removal. Therefore, patients with renal compromise and infants
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`with immature renal function are at risk of Aluminum accumulation. Pregnant women:
`
`The fetus is vulnerable to Aluminum contamination in parenteral nutrition since Aluminum
`
`may be transferred across the placenta. Elderly: Age is a well-known risk factor for renal
`
`impairment and thus results in a higher risk of Aluminum toxicity. Other studies suggest
`
`that Aluminum toxicity may be due to increased absorption of Aluminum due to a
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`weakened GI protective barrier.
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`The compositions and methods described herein provide the means to support the
`
`nutritional needs of patients, including preterm infants or infants with low birth weight, but
`
`reduce the risks associated with Aluminum ingestion. Most preterm and low birth weight
`
`infants tend to require parenteral nutrition with amino acid supplementation during their
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`hospital stay. However, as mentioned above, infants are a particula