DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions and Claim Status
Applicants’ amendments and arguments filed 3/12/26 are acknowledged. Any objection or rejection from the 12/12/25 office action that is not addressed below is withdrawn based on the amendments.
Previously, Group 2 was elected.
Claims 1 and 3-12 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/23/25.
Claim 2 has been canceled.
Claims 13-23 are being examined.
Priority
The priority information is found in the filing receipt of 8/10/23.
Claim Rejections - 35 USC § 112
Claims were previously rejected under 35 USC 112. Since the claims have been amended the rejection is updated to correspond to the instant claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13xi has been amended to recite “purifying Etelcalcetide of step x) by reverse phase HPLC to obtain Etelcalcetide hydrochloride” and claim 13xii refers to adjusting chloride salt content. The specific step of forming the salt is unclear because claim 13xi refers to purifying which is not necessarily the same as forming the salt form. Although claim 18 refers to conversion to the salt it is described as being in addition to the purification. The corresponding conversion step of claim 13 is unclear. Example 5 of the specification refers to etelcalcetide purification (pages 22-23) which seems to correspond in part to claim 13xi. Examples 6-7 of the specification (pages 23-24) refer to the chloride salt and appear to correspond in part to claim 13xii. However, examples 6-7 start with etelcalcetide, not the salt form. It is unclear if the amended claims include new matter because it is not clear that the steps of the claims are matching up with what is provided in the specification. None of the dependent claims clarify the claim scope.
Claim 15 recites ‘concentration’ and then refers to units of ‘ml/g’. Such language is confusing because concentration is typically reported as amount/volume but the units recited in the claim are volume/amount. As such, the scope of the claim is unclear.
The term “chilled” in claim 22 is a relative term which renders the claim indefinite. The term “chilled” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the instant case, it is not clear how to distinguish chilled solutions from those that have not been chilled.
The term “amorphous” in claim 23 is a relative term which renders the claim indefinite. The term “amorphous” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the instant case, it is not clear how to determine whether or not a peptide is considered amorphous.
Although unclear, the claims have been given the broadest reasonable interpretation consistent with the specification and have been interpreted as including no new matter.
The rejection below is a new rejection necessitated by amendment. The previous office action (page 6) expressly stated: “It is unclear if claim 14 is a proper dependent claim” and claim 14 has been amended.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
As amended, claim 14 recites TFA, TIS and DMS which are already required by claim 13vii. Thus, claim 14 merely recites information already required by claim 13.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments - 112
Applicant's arguments filed 3/12/26 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue that the claims have been amended, the amended claims are addressed above.
Although applicants argue that mL/weight is known to denote the volume of cleavage cocktail per weight of peptidyl resin, what is recited in instant claim 15 for example is “concentration of peptidyl resin is 10-30 ml/g”. A concentration of a resin is not the same as the volume of a cleavage cocktail per weight of peptidyl resin. Further, whatever source applicants are referring to has not been provided (for example on an IDS).
Although applicants argue that chilled would mean “cool or cold” and amorphous would mean non-crystalline, no specific definitions or guidance is provided in the instant specification. It is unclear what specific temperature would meet the limitation of “cool or cold” because such determination is subjective. Thus, the phrase “chilled solution” of claim 22 is subjective. With respect to amorphous meaning non-crystalline, it is unclear what other forms (if any) are excluded other than crystalline.
Claim Rejections - 35 USC § 103
Claims were previously rejected under 35 USC 103 based on the references cited below. Since the claims have been amended the rejection is updated to correspond to the instant claims.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 13-20 and 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mohammed et al. (WO 2021/038431 March 4 2021; ‘Mohammed’) in view of Mthembu et al. (‘Breaking a couple: disulfide reducing agents’ ChemBioChem v21 April 30 2020 pages 1947-1954; ‘Mthembu’) in view of Shibue et al. (‘The perchlorate anion is more effective than the trifluoracetate anion as an ion-pairing reagent for reversed-phase chromatography of peptides’ Journal of Chromatography A v1080 2005 pages 49-57; ‘Shibue’) in view of Hazra et al. (US 2011/0236925; ‘Hazra’).
Mohammed teach a process for the preparation of etelcalcetide hydrochloride (abstract and claim 1). Mohammed recognizes the formation of etelcalcetide dimers and impurities (page 2 last paragraph). Mohammed teach a goal of high purity and high yield preparation of etelcalcetide (page 3 first paragraph). Mohammed teach the synthesis of Ac-D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-Arg(pbf)-DArg(pbf)-D-Ala-D-Arg(pbf)-NH-Resin (example 1 on pages 11-12). Mohammed specifically teach the use of Rink amide AM resin and linkage of Fmoc-D-Arg(pbf)-OH (steps A-C on page 11). Mohammed specifically teach deblocking with piperidine (page 12 first paragraph). Mohammed specifically teach coupling with Fmoc-D-Ala with DIC and HOBT in the presence of DMF (page 12 step D 2nd paragraph). Mohammed specifically teach Fmoc deprotections and amino acid couplings were performed sequentially for Fmoc-D-Arg(pbf)-OH, Fmoc-DArg(pbf)-OH, Fmoc-D-Arg(pbf)-OH, Fmoc-D-Ala-OH and Fmoc-D-Cys(Trt)OH, to obtain H-D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-Arg(pbf)-D-Arg(pbf)-D-Ala-D-Arg(pbf)-NH-Resin (page 12 step D 2nd paragraph). Mohammed specifically teach N-acetylation (page 12 step E). Mohammed specifically teach cleaving from the resin (example 2 pages 12-13 connecting paragraph). Mohammed teach that the cocktail mixture is selected from TFA, TIS, DMS and mixtures thereof (page 7 last complete paragraph and claim 3) and in claim 4 recites ‘TFA:TIS:solvent’ as a specific mixture. Mohammed specifically teach the use of 85% TFA and 5% TIS (page 13 first paragraph). Mohammed recognizes the formation of etelcalcetide dimers (page 2 last paragraph) and suggest the inclusion of DTT (claim 3). Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% (page 13 lines 16-26) where acetonitrile and water are used (page 13 lines 16-18). Mohammed teach treatment with cysteine (example 4 pages 13-14 connecting paragraph and claim 1c). Mohammed recognizes the use of hydrogen peroxide for disulphide bond formation (page 2 lines 21-23). Mohammed teach purification via reverse phase HPLC to achieve 99.7% purity (example 5 page 14). Mohammed recognizes precipitation and lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Mohammed specifically recognizes obtaining the etelcalcetide as hydrochloride salt (examples 5 and 8). Mohammed recognizes use of ammonium chloride and HCl for desalting (page 8 lines 16-20 and examples 5 and 8) and recognizes the use of acetonitrile as a solvent (claim 6). Mohammed recognizes the use of cooled components (page 8 line 1). Mohammed recognizes adding water to obtain 20 g/L concentration (page 14 lines 1-2). Mohammed recognizes certain volumes per gram of resin (page 2 lines 10-11).
Mohammed does not specifically recite TCEP in presence of perchloric acid as in step viii of claim 13.
Mthembu recognizes that efficient reduction of disulfide bridges is a requirement for many applications of Cys-containing molecules (abstract). Mthembu teach that TCEP-HCl has multiple advantages over other disulfide reducing agents including a greater reducing capacity than DTT, the reduction is faster and it is not susceptible to oxidation (page 1952 last complete paragraph). Mthembu teach that the properties of TCEP led it to become one to the most extensively used disulfide reducing agents (page 1952 last complete paragraph).
Shibue teach reagents for reversed-phase chromatography of peptides specifically the perchlorate anion for positively charged peptides (title and abstract). Shibue teach that the perchlorate ion is more effective than the trifluoroacetate anion as an ion-pairing reagent (title and abstract) and Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56).
Hazra teach methods of protein purification (title and abstract). Hazra specifically teach the use of perchloric acid pH 3.0 as part of RP-HPLC purification (section 0198).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Mohammed based on the specific teachings and suggestions of Mohammed. Mohammed teach a process for the preparation of etelcalcetide hydrochloride (abstract and claim 1) and recognizes the formation of etelcalcetide dimers and impurities as undesirable (page 2 last paragraph) so one would have been motivated to prepare the peptide using known steps to address such issues. Mohammed teach that the cocktail mixture is selected from TFA, TIS, DMS and mixtures thereof (page 7 last complete paragraph and claim 3) and in claim 4 recites ‘TFA:TIS:solvent’ as a specific mixture so one would have been motivated to make and use such mixtures including TFA:TIS:DMS. Mohammed specifically teach the use of 85% TFA and 5% TIS (page 13 first paragraph) so one would have been motivated to use such amounts (and include DMS at the remaining amount of 10%). Mohammed recognizes the formation of etelcalcetide dimers and impurities as undesirable (page 2 last paragraph). Mohammed recognizes the use of DTT as a reducing agent (claim 3 for example). Since Mthembu teach that TCEP-HCl has multiple advantages over other disulfide reducing agents including a greater reducing capacity than DTT, the reduction is faster and it is not susceptible to oxidation (page 1952 last complete paragraph) one would have been motivated to use TCEP-HCl in the methods of Mohammed. Further, Mohammed teach purification of the etelcalcetide peptide (positively charged due to the presence of multiple arginine) by reverse phase HPLC using gradient mode (page 13 lines 16-26). Mohammed teach etelcalcetide HCl where the hydrochloride is described as xHCl so one would have been motivated to make with suitable x. Shibue teach reagents for reversed-phase chromatography of peptides specifically the perchlorate anion for positively charged peptides (title and abstract). Shibue teach that the perchlorate ion is more effective than the trifluoroacetate anion as an ion-pairing reagent (title and abstract) and Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56). Hazra teach methods of protein purification (title and abstract). Hazra specifically teach the use of perchloric acid pH 3.0 as part of RP-HPLC purification (section 0198). Thus, based on the advantages disclosed one would have been motivated to use the perchloric acid in the method of Mohammed. One would have had a reasonable expectation of success since the components and their functions were known.
In relation to the process and peptide and formula I of claim 13, Mohammed teach a process for the preparation of etelcalcetide hydrochloride where the hydrochloride is described as xHCl (abstract and claim 1) specifically using an Fmoc strategy (example 1 page 11).
In relation to claim 13 step i, Mohammed specifically teach the use of Rink amide AM resin and linkage of Fmoc-D-Arg(pbf)-OH (steps A-C on page 11) which is a polystyrene resin (instant specification page 18 first paragraph).
In relation to claim 13 step ii, Mohammed specifically teach deblocking with piperidine (page 12 first paragraph).
In relation to claim 13 step iiii, Mohammed specifically teach coupling with Fmoc-D-Ala with DIC and HOBT in the presence of DMF (step D first paragraph on page 12).
In relation to claim 13 step iv, Mohammed specifically teach Fmoc deprotections and amino acid couplings were performed sequentially for Fmoc-D-Arg(pbf)-OH, Fmoc-DArg(pbf)-OH, Fmoc-D-Arg(pbf)-OH, Fmoc-D-Ala-OH and Fmoc-D-Cys(Trt)OH, to obtain H-D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-Arg(pbf)-D-Arg(pbf)-D-Ala-D-Arg(pbf)-NH-Resin (page 12 step D 2nd paragraph).
In relation to claim 13 step v, Mohammed specifically teach Fmoc deprotections and amino acid couplings were performed sequentially for Fmoc-D-Arg(pbf)-OH, Fmoc-DArg(pbf)-OH, Fmoc-D-Arg(pbf)-OH, Fmoc-D-Ala-OH and Fmoc-D-Cys(Trt)OH, to obtain H-D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-Arg(pbf)-D-Arg(pbf)-D-Ala-D-Arg(pbf)-NH-Resin (page 12 step D 2nd paragraph).
In relation to claim 13 step vi, Mohammed specifically teach N-acetylation (page 12 step E).
In relation to claim 13 step vii, Mohammed specifically teach cleaving from the resin (example 2 pages 12-13). Mohammed teach that the cocktail mixture is selected from TFA, TIS, DMS and mixtures thereof (page 7 last complete paragraph and claim 3) and in claim 4 recites ‘TFA:TIS:solvent’ as a specific mixture so one would have been motivated to make and use such mixture specifically TFA:TIS:DMS. Mohammed specifically teach the use of 85% TFA and 5% TIS (page 13 first paragraph) so one would have been motivated to use such amounts (and include DMS at the remaining amount of 10%). Mohammed recognizes the formation of etelcalcetide dimers as in instant formula II (page 2 last paragraph). Mohammed recognizes a linear peptide (claim 8 formula IIIa) as in instant formula II.
In relation to claim 13 step viii, Mthembu teach that TCEP-HCl has multiple advantages over other disulfide reducing agents including a greater reducing capacity than DTT, the reduction is faster and it is not susceptible to oxidation (page 1952 last complete paragraph). Mthembu teach that the properties of TCEP led it to become one to the most extensively used disulfide reducing agents (page 1952 last complete paragraph) thus one would have been motivated to use TCEP-HCl in the method of Mohammed. Shibue teach reagents for reversed-phase chromatography of peptides specifically the perchlorate anion for positively charged peptides (title and abstract). Shibue teach that the perchlorate ion is more effective than the trifluoroacetate anion as an ion-pairing reagent (title and abstract) and Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56). Thus, one would have been motivated to use such agent in the method of Mohammed. Hazra teach methods of protein purification (title and abstract). Hazra specifically teach the use of perchloric acid pH 3.0 as part of RP-HPLC purification (section 0198). Since Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56) one would have been motivated to optimize the amount for such effect.
In relation to claim 13 step ix, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% (page 13 lines 16-26) where acetonitrile and water are used (page 13 lines 16-18).
In relation to claim 13 step x, Mohammed teach treatment with cysteine (example 4 pages 13-14). Mohammed recognizes the use of hydrogen peroxide for disulphide bond formation (page 2 lines 21-23).
In relation to claim 13 step xi, Mohammed teach purification via reverse phase HPLC to achieve 99.7% purity (example 5 page 14). Mohammed recognizes reprocessing fractions for greater purity (pages 14-15 connecting paragraph and example 3). Mohammed specifically recognizes obtaining the etelcalcetide as hydrochloride salt (examples 5 and 8).
In relation to claim 13 step xii, Mohammed recognizes precipitation and lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Mohammed specifically recognizes obtaining the etelcalcetide as hydrochloride salt (examples 5 and 8).
In relation to claim 14, Mohammed teach that the cocktail mixture is selected from TFA, TIS, DMS and mixtures thereof (page 7 last complete paragraph and claim 3) and in claim 4 recites ‘TFA:TIS:solvent’ as a specific mixture.
In relation to claim 15, Mohammed recognizes the use of Rink amide resin (example 1) and isolation of linear peptide (example 2). Mohammed recognizes certain volumes per gram of resin (page 2 lines 10-11).
In relation to claim 16, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% (page 13 lines 16-26) where acetonitrile and water are used (page 13 lines 16-18).
In relation to claim 17, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% and yield is greater than 50% (page 13 lines 16-26) where acetonitrile and water are used (page 13 lines 16-18). Shibue teach reagents for reversed-phase chromatography of peptides specifically the perchlorate anion for positively charged peptides (title and abstract). Shibue teach that the perchlorate ion is more effective than the trifluoroacetate anion as an ion-pairing reagent (title and abstract) and Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56). Hazra teach methods of protein purification (title and abstract). Hazra specifically teach the use of perchloric acid pH 3.0 as part of RP-HPLC purification (section 0198).
In relation to claim 18, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% (page 13 lines 16-26). Mohammed recognizes reprocessing fractions for greater purity (pages 14-15 connecting paragraph and example 3).
In relation to claim 19, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% and yield is greater than 50% (page 13 lines 16-26). Mohammed recognizes use of ammonium chloride and HCl for desalting (page 8 lines 16-20 and examples 5 and 8) and recognizes the use of acetonitrile as a solvent (claim 6).
In relation to claim 20, Mohammed recognizes precipitation and lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Mohammed recognizes the use of acetonitrile as a solvent (claim 6).
In relation to claim 22, Mohammed specifically recognizes obtaining the etelcalcetide as hydrochloride salt (examples 5 and 8). Mohammed teach using HCl (page 8 lines 16-20). Mohammed recognizes the use of cooled components (page 8 line 1). Mohammed recognizes adding water to obtain 20 g/L concentration (page 14 lines 1-2) thus recognizing higher concentrations (before dilution).
In relation to claim 23, Mohammed recognizes lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Mohammed recognizes adding water to obtain 20 g/L concentration (page 14 lines 1-2) thus recognizing higher concentrations (before dilution).
Although unclear, the claims have been given the broadest reasonable interpretation consistent with the specification and although unclear the claim limitations as set forth above have been interpreted as being met as discussed above.
Claim(s) 13-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mohammed et al. (WO 2021/038431 March 4 2021; ‘Mohammed’) in view of Mthembu et al. (‘Breaking a couple: disulfide reducing agents’ ChemBioChem v21 April 30 2020 pages 1947-1954; ‘Mthembu’) in view of Shibue et al. (‘The perchlorate anion is more effective than the trifluoracetate anion as an ion-pairing reagent for reversed-phase chromatography of peptides’ Journal of Chromatography A v1080 2005 pages 49-57; ‘Shibue’) in view of Hazra et al. (US 2011/0236925; ‘Hazra’) in view of Yu et al. (US 2010/0285596; ‘Yu’).
Mohammed teach a process for the preparation of etelcalcetide hydrochloride (abstract and claim 1). Mohammed recognizes the formation of etelcalcetide dimers and impurities (page 2 last paragraph). Mohammed teach a goal of high purity and high yield preparation of etelcalcetide (page 3 first paragraph). Mohammed teach the synthesis of Ac-D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-Arg(pbf)-DArg(pbf)-D-Ala-D-Arg(pbf)-NH-Resin (example 1 on pages 11-12). Mohammed specifically teach the use of Rink amide AM resin and linkage of Fmoc-D-Arg(pbf)-OH (steps A-C on page 11). Mohammed specifically teach deblocking with piperidine (page 12 first paragraph). Mohammed specifically teach coupling with Fmoc-D-Ala with DIC and HOBT in the presence of DMF (page 12 step D 2nd paragraph). Mohammed specifically teach Fmoc deprotections and amino acid couplings were performed sequentially for Fmoc-D-Arg(pbf)-OH, Fmoc-DArg(pbf)-OH, Fmoc-D-Arg(pbf)-OH, Fmoc-D-Ala-OH and Fmoc-D-Cys(Trt)OH, to obtain H-D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-Arg(pbf)-D-Arg(pbf)-D-Ala-D-Arg(pbf)-NH-Resin (page 12 step D 2nd paragraph). Mohammed specifically teach N-acetylation (page 12 step E). Mohammed specifically teach cleaving from the resin (example 2 pages 12-13 connecting paragraph). Mohammed teach that the cocktail mixture is selected from TFA, TIS, DMS and mixtures thereof (page 7 last complete paragraph and claim 3) and in claim 4 recites ‘TFA:TIS:solvent’ as a specific mixture. Mohammed specifically teach the use of 85% TFA and 5% TIS (page 13 first paragraph). Mohammed recognizes the formation of etelcalcetide dimers (page 2 last paragraph) and suggest the inclusion of DTT (claim 3). Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% (page 13 lines 16-26) where acetonitrile and water are used (page 13 lines 16-18). Mohammed teach treatment with cysteine (example 4 pages 13-14 connecting paragraph and claim 1c). Mohammed recognizes the use of hydrogen peroxide for disulphide bond formation (page 2 lines 21-23). Mohammed teach purification via reverse phase HPLC to achieve 99.7% purity (example 5 page 14). Mohammed recognizes precipitation and lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Mohammed specifically recognizes obtaining the etelcalcetide as hydrochloride salt (examples 5 and 8). Mohammed recognizes use of ammonium chloride and HCl for desalting (page 8 lines 16-20 and examples 5 and 8) and recognizes the use of acetonitrile as a solvent (claim 6). Mohammed recognizes the use of cooled components (page 8 line 1). Mohammed recognizes adding water to obtain 20 g/L concentration (page 14 lines 1-2). Mohammed recognizes certain volumes per gram of resin (page 2 lines 10-11).
Mohammed does not specifically recite TCEP in presence of perchloric acid as in step viii of claim 13 or the inclusion of acetone as in claim 21.
Mthembu recognizes that efficient reduction of disulfide bridges is a requirement for many applications of Cys-containing molecules (abstract). Mthembu teach that TCEP-HCl has multiple advantages over other disulfide reducing agents including a greater reducing capacity than DTT, the reduction is faster and it is not susceptible to oxidation (page 1952 last complete paragraph). Mthembu teach that the properties of TCEP led it to become one to the most extensively used disulfide reducing agents (page 1952 last complete paragraph).
Shibue teach reagents for reversed-phase chromatography of peptides specifically the perchlorate anion for positively charged peptides (title and abstract). Shibue teach that the perchlorate ion is more effective than the trifluoroacetate anion as an ion-pairing reagent (title and abstract) and Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56).
Hazra teach methods of protein purification (title and abstract). Hazra specifically teach the use of perchloric acid pH 3.0 as part of RP-HPLC purification (section 0198).
Yu teach methods of protein purification (abstract). Yu teach that solvents are chosen such that they may be used to wash through the column and carry away the impurities (section 0143). Yu specifically recites solvents including HCl and acetone and combinations thereof (section 0143).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Mohammed based on the specific teachings and suggestions of Mohammed. Mohammed teach a process for the preparation of etelcalcetide hydrochloride (abstract and claim 1) and recognizes the formation of etelcalcetide dimers and impurities as undesirable (page 2 last paragraph) so one would have been motivated prepare the peptide using known steps to address such issues. Mohammed teach that the cocktail mixture is selected from TFA, TIS, DMS and mixtures thereof (page 7 last complete paragraph and claim 3) and in claim 4 recites ‘TFA:TIS:solvent’ as a specific mixture so one would have been motivated to make and use such mixture specifically TFA:TIS:DMS. Mohammed specifically teach the use of 85% TFA and 5% TIS (page 13 first paragraph) so one would have been motivated to use such amounts (and include DMS at the remaining amount of 10%). Mohammed recognizes the formation of etelcalcetide dimers and impurities as undesirable (page 2 last paragraph). Mohammed recognizes the use of DTT as a reducing agent (claim 3 for example). Since Mthembu teach that TCEP-HCl has multiple advantages over other disulfide reducing agents including a greater reducing capacity than DTT, the reduction is faster and it is not susceptible to oxidation (page 1952 last complete paragraph) one would have been motivated to use TCEP-HCl in the methods of Mohammed. Further, Mohammed teach purification of the etelcalcetide peptide (positively charged due to the presence of multiple arginine) by reverse phase HPLC using gradient mode (page 13 lines 16-26). Mohammed teach etelcalcetide HCl where the hydrochloride is described as xHCl so one would have been motivated to make with suitable x. Shibue teach reagents for reversed-phase chromatography of peptides specifically the perchlorate anion for positively charged peptides (title and abstract). Shibue teach that the perchlorate ion is more effective than the trifluoroacetate anion as an ion-pairing reagent (title and abstract) and Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56). Hazra teach methods of protein purification (title and abstract). Hazra specifically teach the use of perchloric acid pH 3.0 as part of RP-HPLC purification (section 0198). Thus, based on the advantages disclosed one would have been motivated to use the perchloric acid in the method of Mohammed. Yu teach that solvents are chosen such that they may be used to wash through the column and carry away the impurities (section 0143). Yu specifically recites solvents including HCl and acetone and combinations thereof (section 0143). Thus, one would have been motivated to use known agents for the known purpose of removing impurities. One would have had a reasonable expectation of success since the components and their function were known.
In relation to the process and peptide and formula I of claim 13, Mohammed teach a process for the preparation of etelcalcetide hydrochloride where the hydrochloride is described as xHCl (abstract and claim 1) specifically using an Fmoc strategy (example 1 page 11).
In relation to claim 13 step i, Mohammed specifically teach the use of Rink amide AM resin and linkage of Fmoc-D-Arg(pbf)-OH (steps A-C on page 11) which is a polystyrene resin (instant specification page 18 first paragraph).
In relation to claim 13 step ii, Mohammed specifically teach deblocking with piperidine (page 12 first paragraph).
In relation to claim 13 step iiii, Mohammed specifically teach coupling with Fmoc-D-Ala with DIC and HOBT in the presence of DMF (step D first paragraph on page 12).
In relation to claim 13 step iv, Mohammed specifically teach Fmoc deprotections and amino acid couplings were performed sequentially for Fmoc-D-Arg(pbf)-OH, Fmoc-DArg(pbf)-OH, Fmoc-D-Arg(pbf)-OH, Fmoc-D-Ala-OH and Fmoc-D-Cys(Trt)OH, to obtain H-D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-Arg(pbf)-D-Arg(pbf)-D-Ala-D-Arg(pbf)-NH-Resin (page 12 step D 2nd paragraph).
In relation to claim 13 step v, Mohammed specifically teach Fmoc deprotections and amino acid couplings were performed sequentially for Fmoc-D-Arg(pbf)-OH, Fmoc-DArg(pbf)-OH, Fmoc-D-Arg(pbf)-OH, Fmoc-D-Ala-OH and Fmoc-D-Cys(Trt)OH, to obtain H-D-Cys(Trt)-D-Ala-D-Arg(pbf)-D-Arg(pbf)-D-Arg(pbf)-D-Ala-D-Arg(pbf)-NH-Resin (page 12 step D 2nd paragraph).
In relation to claim 13 step vi, Mohammed specifically teach N-acetylation (page 12 step E).
In relation to claim 13 step vii, Mohammed specifically teach cleaving from the resin (example 2 pages 12-13). Mohammed teach that the cocktail mixture is selected from TFA, TIS, DMS and mixtures thereof (page 7 last complete paragraph and claim 3) and in claim 4 recites ‘TFA:TIS:solvent’ as a specific mixture so one would have been motivated to make and use such mixture specifically TFA:TIS:DMS. Mohammed specifically teach the use of 85% TFA and 5% TIS (page 13 first paragraph) so one would have been motivated to use such amounts (and include DMS at the remaining amount of 10%). Mohammed recognizes the formation of etelcalcetide dimers as in instant formula II (page 2 last paragraph). Mohammed recognizes a linear peptide (claim 8 formula IIIa) as in instant formula II.
In relation to claim 13 step viii, Mthembu teach that TCEP-HCl has multiple advantages over other disulfide reducing agents including a greater reducing capacity than DTT, the reduction is faster and it is not susceptible to oxidation (page 1952 last complete paragraph). Mthembu teach that the properties of TCEP led it to become one to the most extensively used disulfide reducing agents (page 1952 last complete paragraph) thus one would have been motivated to use TCEP-HCl in the method of Mohammed. Shibue teach reagents for reversed-phase chromatography of peptides specifically the perchlorate anion for positively charged peptides (title and abstract). Shibue teach that the perchlorate ion is more effective than the trifluoroacetate anion as an ion-pairing reagent (title and abstract) and Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56). Thus, one would have been motivated to use such agent in the method of Mohammed. Hazra teach methods of protein purification (title and abstract). Hazra specifically teach the use of perchloric acid pH 3.0 as part of RP-HPLC purification (section 0198). Since Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56) one would have been motivated to optimize the amount for such effect.
In relation to claim 13 step ix, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% (page 13 lines 16-26) where acetonitrile and water are used (page 13 lines 16-18).
In relation to claim 13 step x, Mohammed teach treatment with cysteine (example 4 pages 13-14). Mohammed recognizes the use of hydrogen peroxide for disulphide bond formation (page 2 lines 21-23).
In relation to claim 13 step xi, Mohammed teach purification via reverse phase HPLC to achieve 99.7% purity (example 5 page 14). Mohammed recognizes reprocessing fractions for greater purity (pages 14-15 connecting paragraph and example 3). Mohammed specifically recognizes obtaining the etelcalcetide as hydrochloride salt (examples 5 and 8).
In relation to claim 13 step xii, Mohammed recognizes precipitation and lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Mohammed specifically recognizes obtaining the etelcalcetide as hydrochloride salt (examples 5 and 8).
In relation to claim 14, Mohammed teach that the cocktail mixture is selected from TFA, TIS, DMS and mixtures thereof (page 7 last complete paragraph and claim 3) and in claim 4 recites ‘TFA:TIS:solvent’ as a specific mixture.
In relation to claim 15, Mohammed recognizes the use of Rink amide resin (example 1) and isolation of linear peptide (example 2). Mohammed recognizes certain volumes per gram of resin (page 2 lines 10-11).
In relation to claim 16, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% (page 13 lines 16-26) where acetonitrile and water are used (page 13 lines 16-18).
In relation to claim 17, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% and yield is greater than 50% (page 13 lines 16-26) where acetonitrile and water are used (page 13 lines 16-18). Shibue teach reagents for reversed-phase chromatography of peptides specifically the perchlorate anion for positively charged peptides (title and abstract). Shibue teach that the perchlorate ion is more effective than the trifluoroacetate anion as an ion-pairing reagent (title and abstract) and Shibue teach predictable nature of the effect of increasing perchlorate concentration on the retention behaviour of positively charged peptides (section 4 page 56). Hazra teach methods of protein purification (title and abstract). Hazra specifically teach the use of perchloric acid pH 3.0 as part of RP-HPLC purification (section 0198).
In relation to claim 18, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% (page 13 lines 16-26). Mohammed recognizes reprocessing fractions for greater purity (pages 14-15 connecting paragraph and example 3).
In relation to claim 19, Mohammed teach purification of the peptide by reverse phase HPLC using gradient mode where the purity is 98.48% and yield is greater than 50% (page 13 lines 16-26). Mohammed recognizes use of ammonium chloride and HCl for desalting (page 8 lines 16-20 and examples 5 and 8) and recognizes the use of acetonitrile as a solvent (claim 6).
In relation to claim 20, Mohammed recognizes precipitation and lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Mohammed recognizes the use of acetonitrile as a solvent (claim 6).
In relation to claim 21, Mohammed recognizes precipitation and lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Yu teach that solvents are chosen such that they may be used to wash through the column and carry away the impurities (section 0143). Yu specifically recites solvents including HCl and acetone and combinations thereof (section 0143). Thus, one would have been motivated to use known agents for the known purpose of removing impurities.
In relation to claim 22, Mohammed specifically recognizes obtaining the etelcalcetide as hydrochloride salt (examples 5 and 8). Mohammed teach using HCl (page 8 lines 16-20). Mohammed recognizes the use of cooled components (page 8 line 1). Mohammed recognizes adding water to obtain 20 g/L concentration (page 14 lines 1-2) thus recognizing higher concentrations (before dilution).
In relation to claim 23, Mohammed recognizes lyophilization as known steps in production of the peptide (page 2 lines 9-14, pages 7-8 connecting paragraph and examples 2-3). Mohammed recognizes adding water to obtain 20 g/L concentration (page 14 lines 1-2) thus recognizing higher concentrations (before dilution).
Although unclear, the claims have been given the broadest reasonable interpretation consistent with the specification and although unclear the claim limitations as set forth above have been interpreted as being met as discussed above.
Response to Arguments - 103
Applicant's arguments filed 3/12/26 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue that Mohammed alone does not anticipate the claims, the instant rejection is a multiple reference 103 rejection and as such any single reference does not necessarily anticipate the claims. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Although applicants argue that Mohammed does not teach the use of TCEP, Mohammed recognizes the formation of etelcalcetide dimers as a problem (page 2 last paragraph) and suggest the inclusion of DTT (claim 3). Mthembu recognizes that efficient reduction of disulfide bridges is a requirement for many applications of Cys-containing molecules (abstract). Mthembu teach that TCEP-HCl has multiple advantages over other disulfide reducing agents including a greater reducing capacity than DTT, the reduction is faster and it is not susceptible to oxidation (page 1952 last complete paragraph). Mthembu teach that the properties of TCEP led it to become one to the most extensively used disulfide reducing agents (page 1952 last complete paragraph). Mohammed teach a process for the preparation of etelcalcetide hydrochloride (abstract and claim 1) and recognizes the formation of etelcalcetide dimers and impurities as undesirable (page 2 last paragraph) so one would have been motivated prepare the peptide using known steps to address such issues.
Although applicants provide a schematic (page 12 of reply of 3/12/26) which alleges to be the claimed invention, instant claim 13 requires steps i-xii. The schematic (page 12 of reply 3/12/26) does not show all of the instant steps required by claim 13 and there is no reasonable basis to equate it to the claimed invention.
Although applicants argue that Mohammed recognizes the formation of dimers in the background section, MPEP 2123 recognizes that references are relevant for all they contain. Thus, the specific location that the information is provided does not lead to a teaching away.
Although applicants argue that the inventors were the first to recognize when the dimer forms, the instant claims are not drawn to the determination of when the dimer is formed. The claims are drawn to methods of synthesis of etelcalcetide hydrochloride.
Although applicants allege that at best Mohammed shares only one step in common with the claimed process, as noted above claim 13 recites steps i-xii. In relation to claim 13 step i, Mohammed specifically teach the use of Rink amide AM resin and linkage of Fmoc-D-Arg(pbf)-OH (steps A-C on page 11). In relation to claim 13 step ii, Mohammed specifically teach deblocking with piperidine (page 12 first paragraph), etc. Thus, applicants assertion is not correct for at least these reasons.
Although applicants argue that one would not have been motivated to modify Mohammed, Mohammed recognizes the formation of etelcalcetide dimers as a problem (page 2 last paragraph). Further, the process of Mohammed requires contacting with L-Cysteine (claim 1c). If no free cysteine is available then the contacting in L-Cysteine will not result in the desired product.
Conclusion
Applicant's amendment necessitated any new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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RONALD T. NIEBAUER
Primary Examiner
Art Unit 1658
/RONALD T NIEBAUER/Examiner, Art Unit 1658
Prosecution Insights