DocCode — SCORE
`
`SCORE Placeholder Sheet for IFW Content
`
`Application Number: 16248460
`
`Document Date: 01/15/2019
`
`The presence ofthis form in the IFW record indicates that the following document type was received
`in electronic format on the date identified above. This content is stored in the SCORE database.
`
`Since this was an electronic submission, there is no physical artifact folder, no artifact folder is
`recorded in PALM, and no paper documentsor physical media exist. The TIFF images in the IFW
`record were created from the original documents that are stored in SCORE.
`
`Drawing
`
`At the time of documententry (noted above):
`e USPTO employees may access SCORE content via eDAN using the Supplemental Content
`tab, or via the SCORE webpage.
`e External customers may access SCORE content via PAIR using the Supplemental Content
`tab.
`
`Form Revision Date: August 26, 2013
`
`NexusEx. 1024
`Page 1 of 466
`
`Nexus Ex. 1024
`Page 1 of 466
`
`

`

`Doc Code: TRACK1.REQ
`DocumentDescription: TrackOne Request
`
`PTO/AIA/424 (04-14)
`
`CERTIFICATION AND REQUESTFOR PRIORITIZED EXAMINATION
`UNDER37 CFR1.102(e) (Page1of 1)
`
`[imener’’ [John Maloney omLT
`knoe Application Number(if
`First Named
`STABLE, HIGHLY PURE L-CYSTEINE COMPOSITIONS FOR INJECTION AND METHODS OF USE
`
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTSPRIORITIZED 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
`becausethat fee, set forth in 37 CFR 1.18(d), is currently $0. The basicfiling fee, search fee,
`and examination fee are filed with the request or have been already been paid.
`| understand
`that any required excess claims fees or application size fee must be paid for the application.
`
`| understand that the application may not contain, or be amended to contain, more than four
`independentclaims, more thanthirty total claims, or any multiple dependent claims, and that
`any request for an extension of time will cause an outstanding Track | request to be dismissed.
`
`3.
`
`The applicable box is checked below:
`
`Original Application (Track One)
`
`- Prioritized Examination under §
`
`(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.
`
`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.
`
`Registration Number
`
`A requestfor continued examination has been filed with, or prior to, this form.
`If the applicationis a utility application, this certification and requestis being filed via EFS-Web.
`iii. The application is an original nonprovisionalutility 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 requestis being filed prior to the mailing of a first Office action responsive
`to the request for continued examination.
`No prior request for continued examination has been granted prioritized examination status
`under 37 CFR 1.102(e)(2).
`
`Signature
`
`/pryan I. skelton/
`
`Bryan L. Skelton
`
`pate Yanuary 15, 2019
`
`Practitioner
`
`50893
`
`NexusEx. 1024
`Page 2 of 466
`
`Nexus Ex. 1024
`Page 2 of 466
`
`

`

`Privacy Act Statement
`
`The Privacy Act of 1974 (P.L. 93-579) requires that you be given certain information in connection with your
`submission of the attached form related to a patent application or patent. Accordingly, pursuant to the requirements of
`the Act, please be advised that: (1) the general authority for the collection of this information is 35 U.S.C. 2(b)(2); (2)
`furnishing of the information solicited is voluntary; and (3) the principal purpose for which the information is used by the
`U.S. Patent and Trademark Office is to process and/or examine your submission related to a patent application or
`patent.
`If you do not furnish the requested information, the U.S. Patent and Trademark Office may not be able to
`process and/or examine your submission, which mayresult in termination of proceedings or abandonmentof the
`application or expiration of the patent.
`
`The information provided by youin this form will be subject to the following routine uses:
`
`1.
`
`Theinformation on this form will be treated confidentially to the extent allowed under the Freedom of
`Information Act (5 U.S.C. 552) and the Privacy Act (5 U.S.C 552a). Records from this system of records may
`be disclosed to the Department of Justice to determine whetherdisclosure of these records is required by the
`Freedom of Information Act.
`A record from this system of records may bedisclosed, as a routine use, in the course of presenting evidence
`to a court, magistrate, or administrative tribunal, including disclosures to opposing counselin the course of
`settlement negotiations.
`A record in this system of records may be disclosed, as a routine use, to a Memberof Congress submitting a
`requestinvolving an individual, to whom the record pertains, whentheindividual has requested assistance from
`the Memberwith respect to the subject matter of the record.
`A record in this system of records may be disclosed, as a routine use, to a contractor of the Agency having
`needfor the informationin order to perform a contract. Recipients of information shall be required to comply
`with the requirements of the Privacy Act of 1974, as amended, pursuant to 5 U.S.C. 552a(m).
`A record related to an International Application filed under the Patent Cooperation Treaty in this system of
`records may be disclosed, as a routine use, to the International Bureau of the World Intellectual Property
`Organization, pursuant to the Patent Cooperation Treaty.
`A record in this system of records maybe disclosed, as a routine use, to another federal agency for purposes
`of National Security review (35 U.S.C. 181) and for review pursuantto the Atomic Energy Act (42 U.S.C.
`218(c)).
`A record from this system of records maybedisclosed, as a routine use, to the Administrator, General
`Services, or his/her designee, during an inspection of records conducted by GSA aspart of that agency’s
`responsibility to recommend improvements in records managementpractices and programs,under authority of
`44 U.S.C. 2904 and 2906. Such disclosure shall be made in accordance with the GSA regulations governing
`inspection of records for this purpose, and anyotherrelevant(/.e., GSA or Commerce) directive. Such
`disclosure shall not be used to make determinations aboutindividuals.
`A record from this system of records may bedisclosed, as a routine use, to the public after either publication of
`the application pursuant to 35 U.S.C. 122(b) or issuance of a patent pursuant to 35 U.S.C. 151. Further, a
`record may bedisclosed, subject to the limitations of 37 CFR 1.14, as a routine use, to the public if the record
`wasfiled in an application which became abandonedorin which the proceedings were terminated and which
`application is referenced by either a published application, an application open to public inspection or an issued
`patent.
`A record from this system of records may be disclosed, as a routine use, to a Federal, State, or local law
`enforcement agency,if the USPTO becomes aware ofa violation or potential violation of law or regulation.
`
`NexusEx. 1024
`Page 3 of 466
`
`Nexus Ex. 1024
`Page 3 of 466
`
`

`

`STABLE, HIGHLY PURE L-CYSTEINE COMPOSITIONS FOR INJECTION AND
`
`Atty. Ref. No. 066859/509450
`
`METHODSOF USE
`
`TECHNICAL FIELD
`
`The subject matter described herein relates generally to compositions for parenteral
`
`administration comprising L-cysteine that are stable and have desirable safety attributes
`
`for extended periodsoftime.
`
`BACKGROUND
`
`L-cysteine is a sulfur-containing amino acid that can be synthesized de novo
`
`10
`
`from methionine and serine in adult humans. L-cysteine performs a variety of
`
`metabolic functions. For example, L-cysteine is involved in growth and protein
`
`synthesis and it is a precursor for glutathione, an important intracellular antioxidant.
`
`L-cysteine is generally classified as a non-essential amino acid or “semi-
`
`essential” amino acid because it can be synthesized in small amounts by the human
`
`15
`
`body. However, some adults can still benefit from L-cysteine supplementation.
`
`Further, L-cysteine has been classified as conditionally essential in some cases. For
`
`example, L-cysteine can be conditionally essential
`
`in preterm infants due to
`
`biochemical immaturity of the enzyme cystathionase that is involved in L-cysteine
`
`synthesis.
`
`Thus,
`
`there are a number of circumstances in which L-cysteine
`
`20
`
`supplementation can be desirable.
`
`The subject matter described herein addresses the shortcomings of the art by
`
`providing L-cysteine compositions that facilitate the desired supplementation but
`
`with an exceptional safety, purity and stability profile.
`
`BRIEF SUMMARY
`
`25
`
`In certain aspects, the subject matter described herein is directed to a safe, stable L-
`
`cysteine composition for parenteral administration, comprising:
`
`NexusEx. 1024
`Page 4 of 466
`
`Nexus Ex. 1024
`Page 4 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in
`
`an amount from about 10 mg/mL to about 100 mg/mL;
`
`Aluminum (AJ) in an amount from about 1.0 part 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-
`
`cysteine;
`
`pyruvic acid in an amount from about 0.001 wt% to about 2.0 wt% relative to L-
`
`cysteine;
`
`a pharmaceutically acceptable carrier, comprising water;
`
`headspace O2 that is from about 0.5% to 4.0% from the time of manufacture to
`
`about 1 month from manufacture when stored at room temperature;
`
`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
`
`1 month from
`
`manufacture when stored at room temperature,
`
`wherein the composition is enclosed in a single-use container having a volume of
`
`10
`
`15
`
`from about 10 mL to about 100 mL.
`
`In certain aspects, the subject matter described herein is directed to a safe, stable L-
`
`cysteine composition for parenteral administration, comprising:
`
`L-cysteine or a pharmaceutically acceptable salt thereof and/or hydrate thereof in
`
`20
`
`an amount from about 10 mg/mL to about 100 mg/mL;
`
`Aluminum (AJ) 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-
`
`cysteine;
`
`25
`
`pyruvic acid in an amount from about 0.001 wt% to about 2.0 wt% relative to L-
`
`cysteine;
`
`a pharmaceutically acceptable carrier, comprising water;
`
`headspace O2 that is from about 0.5% to 4.0% from the time of manufacture to
`
`about 1 month from manufacture when stored at room temperature;
`
`NexusEx. 1024
`Page 5 of 466
`
`Nexus Ex. 1024
`Page 5 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`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
`
`1 month from
`
`manufacture when stored at room temperature,
`
`optionally one or more metals selected from the group consisting of Lead from
`
`about 1.0 ppb to about 10 ppb, Nickel from about 5 ppb to about 40 ppb, Arsenic from
`
`about 0.1 ppb to 10 ppb, and Mercury [rom about 0.2 ppb to about 5.0 ppb;
`
`wherein the composition is enclosed in a single-use container having a volume of
`
`from about 10 mL to about 100 mL.
`
`In certain aspects, the subject matter described herein is directed to a safe, stable
`
`10
`
`composition from about 100 mL to about 1000 mL for administration via a parenteral
`
`infusion within about 24 to about 48 hours of admixture, comprising a mixture of a
`
`composition of L-Cysteine described herein; and an amino acid composition that is
`
`essentially free of L-Cysteine comprising one or more aminoacidsselected from the group
`
`consisting of:
`
`leucine,
`
`isoleucine,
`
`lysine, valine, phenylalanine, histidine,
`
`threonine,
`
`15
`
`methionine, tryptophan, alanine, arginine, glycine, proline, serine, and tyrosine.
`
`20
`
`25
`
`In certain aspects, the subject matter described herein is directed to a method of
`
`reducing Aluminum administration from a total parenteral nutrition regimen comprising
`
`L-cysteine, the method comprising, mixing a composition comprising L-cysteine or a
`
`pharmaceutically acceptable salt thereof and/or hydrate thereof comprising:
`
`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-
`
`cysteine; and
`
`pyruvic acid in an amount from about 0.001 wt% to about 2.0 wt% relative to L-
`
`cysteine;
`
`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, proline, serine, and tyrosine; and
`
`a pharmaceutically acceptable carrier, comprising water,
`
`to form a composition for infusion having a volume of about 100 mL to about 1000 mL,
`
`NexusEx. 1024
`Page 6 of 466
`
`Nexus Ex. 1024
`Page 6 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`wherein the Aluminum provided in said parenteral nutrition regimenis from about 1-2 to
`
`about 4-5 micrograms/kg/day.
`
`In certain aspects, the subject matter described herein is directed to methods of
`
`treating a subject having an adverse health condition that is responsive to L-cysteine
`
`administration, comprising:
`
`diluting a stable L-cysteine composition as described herein with an intravenous
`
`fluid to prepare a diluted L-cysteine composition for infusion; and
`
`infusing the diluted L-cysteine composition for infusion to a subject to provide a
`
`therapeutically effective dose of L-cysteine or a pharmaceutically acceptable salt thereof
`
`10
`
`and/or hydrate thereof to the subject in a therapcutically effective dosing regimen.
`
`In certain aspects, the subject matter described herein are directed to methods of
`
`admuinistermg L-Cysteine together with a composition for parenteral nutrition, comprising:
`
`diluting a stable L-cysteine composition for injection as described herein with a
`
`parenteral nutrition composition to form a mixture; and
`
`15
`
`parenterally administering the mixture to a subject
`
`in need thereof in a
`
`therapeutically and/or nutritionally cffective 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
`
`0.5 kilos to about 2.0 kilos. In another aspect, the subject is a pediatric patient that is of
`
`about 1 month to six months of age. Some of these subjects may weigh from about 0.2
`
`20
`
`kilos to about 20 kilos. In another aspect, the subject is an adult requiring parenteral
`
`nutrition.
`
`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
`
`25
`
`demonstrate the effectiveness of the Head Space Reduction (HSR) cycle in allaming
`
`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
`
`NexusEx. 1024
`Page 7 of 466
`
`Nexus Ex. 1024
`Page 7 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`finally a reduction of dissolved oxygen to an average of 0.50 ppm after headspace
`
`reduction. This demonstrates the specific phase of manufacturing at which and to the
`
`specific level that oxygen needs to be controlled in the product.
`
`Figure 2 depicts the overall
`
`trend of the results from the experiments that
`
`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
`
`10
`
`finally a reduction of dissolved oxygen to an average of 0.50 ppm after headspace
`
`reduction.
`
`Figure 3 depicts a process filler set up to fill and reduce head space oxygen.
`
`Figure 4 shows data for the process of Example 4. The plot shows comparison of
`
`oxygen headspace control between the lyophilizer chamber headspace control method
`
`15
`
`versus the high-speed filler vacuum stoppering system. The time zero oxygen headspace
`
`results
`
`for
`
`the batch PROT-000213 are shown in comparison to the previously
`
`manufactured lots. Results shown were measured at the time of manufacturing on samples
`
`of vials from the batches.
`
`Figure 5 depicts the data measured for dissolved oxygen levels in the process of
`
`20
`
`Example 4.
`
`DETAILED DESCRIPTION
`
`The presently disclosed subject matter will now be described more fully hereinafter.
`
`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
`
`25
`
`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
`
`NexusEx. 1024
`Page 8 of 466
`
`Nexus Ex. 1024
`Page 8 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`and other embodiments are intended to be included within the scope of the appended
`
`claims.
`
`In other words,
`
`the subject matter described herein covers all alternatives,
`
`modifications, and equivalents that are within the ordinary skill in the art. In the event that
`
`one or more of the incorporated literature, patents, and similar materials differs from or
`
`contradicts this application,
`
`including but not
`
`limited to defined terms,
`
`term usage,
`
`described techniques, or the like, this application controls. Unless otherwise defined, all
`
`technical and scientific terms used herein are intended to have the same meaning as
`
`commonly understood by one of ordinary skill in this field. All publications, patent
`
`applications, patents, and other references mentioned herein are incorporated by reference
`
`10
`
`in their entirety.
`
`Advantageously,
`
`it has been found that the desirable attributes of L-cysteine
`
`compositions for infusion can be obtained without the characteristic impurity profile that
`
`is known in the art. Such impurity profile makes the product less safe to be used by
`
`patients, in particular, preterm and term infants and pediatric patients of 1 month to 1 year
`
`15
`
`as well ascritically ill adults. Specifically, the art formulations fail to address the issues
`
`related to the amounts of Aluminum and cystine, among other impurities, that can be
`
`routinely present and co-administered with L-cysteine.
`
`It has now been found that L-
`
`cysteine compositions for injection can be prepared using the methods described herein
`
`whereby the compositions unexpectedly comprise exceedingly low levels of Aluminum
`
`20
`
`and other undesirable impurities, such as cystine, pyruvic acid, certain heavy metals and
`
`certain ions. As a result, the present compositions and methods of using said compositions
`
`are safer to the intended subject compared to the currently available compositions and
`
`methods. Further, the product is also rendered more stable by virtue of lower levels of
`
`cystine generated by the manufacturing processes described herein.
`
`25
`
`As described herein, without being bound to theory, it has been found that the
`
`problemsof 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
`
`oxygen in the headspace as well as certain heavy metals and certain ions that may leach or
`
`be extracted out of the container closure.
`
`NexusEx. 1024
`Page 9 of 466
`
`Nexus Ex. 1024
`Page 9 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`An L-Cysteine for injection product was prepared with the aim to provide a product
`
`that would be acceptable for administration to infants, pediatric and adult patients. High
`
`quality Schott glass vials and stoppers were used. See Example 2. It was however found
`
`that glass containers contribute more significantly than expected to the Aluminum content
`
`of L-cysteine compositions stored therein to the point where the product did not meet the
`
`specifications for certain components. Products having such Alumimum levels would
`
`likely be deemed unsafe by the FDA. Assuch, efforts were focused on identifying the
`
`sources of Aluminum in the product and attempts to minimize it in the product. These
`
`efforts led to the unexpected discovery that simply removing a source of Aluminum by
`
`10
`
`replacing glass with plastic did not result in a product having the desired propcrtics.
`
`Additional efforts to identify the root cause for the productfailure led to the finding
`
`that the product likely failed because oxygen entered the plastic container and into the
`
`product at a rate higher than previously expected or predicted. For example, the plastic
`
`container product failed in somecasesin less than 1-2 months. See Example 3. This finding
`
`15
`
`was also unexpected. Increased oxygenlevels in the product led to unacceptable levels of
`
`oxidation products, such as cystine, which precipitated and caused particulates in the
`
`product. Particulates are dangerous in injectable compositions and create a safety concern,
`
`in addition to the stability issuc to the product.
`
`However, the precipitation may have been exacerbated by reduction in Aluminum
`
`20
`since Aluminum in solution may haveastabilizing effect. Consequently, removing
`
`Aluminum may have the unintended consequenceof increased precipitation and product
`
`failure in the presence of even small amounts of oxygen in the container. This was
`
`unexpected.
`
`Additionally, controlling heat in the process including during the compounding
`
`25
`
`and/orsterilization 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 productis subjected to terminal
`
`sterilization which exposes the product to high temperatures such as 120 °C.
`
`NexusEx. 1024
`Page 10 of 466
`
`Nexus Ex. 1024
`Page 10 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`Some subjects that would be receiving L-Cysteine supplementation are, as
`
`discussed elsewhere herein, pre-term neonatesor full-term infants that are underweight, or
`
`infants that may be full term and are not underweightbutarestill candidates for treatment,
`
`in many cases for longer term treatment. For example, some of these subjects may be
`
`treated with L-Cysteine for several days or several weeks, even several months. In these
`
`cases, il is imperative that the subjects are not exposed to potentially toxic or undesirable
`
`levels of some anions and heavy metals that may be present in drug products. Examples of
`
`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
`
`10
`
`of these are introduced into drug products through manufacturing processes, containcr
`
`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 maybe notas vulnerable as in the case of L-Cysteine, or the dosing of
`
`such drug products may be very limited, i.e., for one or a few doses. For the reasons noted
`
`15
`
`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
`
`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
`
`20
`
`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 climinating heat in the process, and in consideration of
`
`data showing selection of the appropriate container,
`
`stopper, drug substance, and
`
`excipients,
`
`individually or in combinalion(s),
`
`resulted in achieving
`
`a sale, stable
`
`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
`
`weigh as low as 0.5 kilos, for a few days to several weeks.
`
`NexusEx. 1024
`Page 11 of 466
`
`Nexus Ex. 1024
`Page 11 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`L-cysteine for injection is a marketed product used as a componentofa nutritional
`
`supplementregimenreferredto 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,
`
`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 Potasstum Phosphate, Calcium gluconate, and
`
`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).
`
`10
`
`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
`
`in mimimizing the Aluminum levels coming from L-Cysteine compositions so thal when
`
`admixed with other ingredients of TPN admixtures, the overall Aluminum levels could be
`
`reduced while minimizing introduction of undesirable materials such as heavy metals,
`
`15
`
`anions, and particulates. All of these components are present in amounts that are below
`
`levels determined to besafe.
`
`L-cysteine (2-Amino-3-sulfhydrylpropanoic acid} is a sulfur-containing amino
`
`acid having a structure according to Formula I:
`
`OQ
`
`HS
`
`OH
`
`20
`
`L-cysteine performs a variety of metabolic functions. For example, L-cysteine is a
`
`precursorfor antioxidants, such as glutathione and taurine, thal support oxidative defense
`
`and a healthy immune system. L-cysteine can also play a role in the synthesis of essential
`
`fatty acids and facilitate production of cell membranes and protective covers of nerve
`
`endings. Additionally, L-cysteine can be an important precursor for many proteins, such
`
`25
`
`as structural proteins in connective tissuc. Thus, the depletion or absence of cystathionase
`
`activity in premature fetuses and newborns to synthesize L-cysteine de novo has led to the
`
`NexusEx. 1024
`Page 12 of 466
`
`Nexus Ex. 1024
`Page 12 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`categorization of L-cysteine as a conditionally essential amino acid. Additionally,
`
`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.
`
`Knownpharmaceutical compositions that contain L-cysteine can typically contain
`
`undesirable levels of certain components. Cystine is an oxidation product of L-cysteine.
`
`Like L-cysteine, cystine can be synthesized in the liver. Further, both L-cysteine and
`
`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
`
`time. Thus, it may be desirable to maintain the amount of cystine within predetermined
`
`10
`
`levels over time. Forall 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
`
`pyruvic acid within predetermined levels over time.
`
`15
`
`Perhaps of most concern is
`
`the level of Aluminum in known L-cysteine
`
`compositions. Aluminumcontamination and associated Aluminumtoxicity can lead to a
`
`numberof 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
`
`20
`
`on the conservative side as much as possible, ie., at 4 mcg/kg/day to avoid accidental
`
`overdosing in case Aluminum from some other reason (unanticipated or unknown source
`
`or due to humanerror) 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
`
`25
`
`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, orless than 20 ppb,orless than10 ppb, orless than 5 ppb, orless than 1.0 ppb. Thus,
`
`30
`
`what has now been achieved is an unexpected and substantial reduction in Aluminum
`
`10
`
`NexusEx. 1024
`Page 13 of 466
`
`Nexus Ex. 1024
`Page 13 of 466
`
`

`

`Atty. Ref. No. 066859/509450
`
`content of an L-Cysteine composition that permits exposure to less than or equal to 4-5
`
`microgramsper kilogram per day (ug/kg/d) to avoid or minimize Aluminum toxicity while
`
`still providing therapeutically effective L-cysteine in a stable composition. In someaspects,
`
`the compositions described herein permit an Aluminum dose of as
`
`low as 0.6
`
`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
`
`10
`
`with immature renal function are at risk of Aluminum accumulation. Pregnant women:
`
`The fetus is vulnerable to Aluminum contaminationin parenteral nutrition since Aluminum
`
`may be transferred across the placenta. Elderly: Age is a well-knownrisk factor for renal
`
`impairment and thus results in a higher risk of Aluminum toxicity. Other studies suggest
`
`that Aluminum toxicily may be due to increased absorption of Aluminum due to a
`
`15
`
`weakened GIprotective barrier.
`
`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
`
`20
`
`hospital stay. However, as mentioned above,infants are a particularly high-risk population
`
`for Aluminum toxicity. To address such issues, in certain embodiments, the compositions
`
`comprise about 34.5 mg/mL of L-cysteine (measuredas a base, i.e., nol measured as HCl
`
`and monohydrate) and no more than 250 ppb, preferably about 120 ppb, or lower, of
`
`Aluminum. These compositions with no more than 120 ppb of Aluminum,and in certain
`
`25
`
`embodiments, about 120 ppb, or 100 ppb, or 80 ppb, or 60 ppb, or 50 ppb, or 20 ppb, or 10
`
`ppb or 5 ppb or 1.0 ppb, or any suitable subrange encompassing the specific values, in units
`
`of 5 ppb, permit great flexibility with respect to the amino acid supplementation for TPN
`
`preparations.
`
`