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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 12/21/25 has been entered.
Election/Restrictions and Claim Status
Applicants’ amendments and arguments filed 12/21/25 are acknowledged. Any objection or rejection from the 9/23/25 office action that is not addressed below is withdrawn based on the amendments and/or arguments.
37 CFR 1.121(c) sets forth the manner or making amendments. In the instant case claim, Claims 8-9 of 7/25/25 did not show any text and were not in accord with 37 CFR 1.121(c). Currently, claim 8-9 are listed as withdrawn and have been treated as being withdrawn
Previously, Group 1 was elected.
Claims 8-9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as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.
Election was made without traverse in the reply filed on 3/9/25.
Claims 1-7 are being examined.
Priority
The priority information is found in the filing receipt dated 6/14/22.
Specification
The amendment filed 12/21/25 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: The specification has been amended to recite ‘x has a value of 4-5’ specifically with respect to CH3COOH. The phrase ‘x has a value of 4-5’ could not be located in the original application and the arguments do not point to any location or reasoning for support for the amendment with respect to CH3COOH (arguments related to HCl are not necessarily relevant to arguments about CH3COOH).
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Rejections - 35 USC § 112
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 1-7 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 1d has been amended to refer to ‘elution using dilute HCl’. The specification refers to elution using very dilute HCl (page 8 lines 18-19) . It is unclear if any degree of dilution is acceptable. It is not clear if claim 1 includes new matter since very dilute is not necessarily the same a dilute. None of the dependent claims clarify the claim scope.
Although unclear the claims have been given the broadest reasonable interpretation consistent with the specification.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection is a ‘new matter’ rejection. Section 2163 of the MPEP states: ‘While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure’.
Claim 1 has been amended to recite ‘elution using dilute HCl’. The specification refers to elution using very dilute HCl (page 8 lines 18-19). Elution using dilute HCl would seem to be broader than elution using very dilute HCl. All of the dependent claims incorporate the same limitation.
Claim 1 has been amended to recite ‘x has a value of 4-5’ (page 2 of claims) specifically with respect to CH3COOH. The phrase ‘x has a value of 4-5’ could not be located in the original application and the arguments do not point to any location or reasoning for support for the amendment with respect to CH3COOH (arguments related to HCl are not necessarily relevant to arguments about CH3COOH). As such, there is no reason to conclude that claims 1-7 are supported in the specification through express, implicit, or inherent disclosure for at least the reasons discussed above.
As such, there is no reason to conclude that claims 1-7 are supported in the specification through express, implicit, or inherent disclosure for at least the reasons discussed above.
Response to Arguments - 112
Applicant's arguments filed 12/21/25 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue that claims have been amended, the amended claims are addressed above.
Claim Rejections - 35 USC § 103
Claims were previously rejected 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) 1-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bezemer et al. (WO 2015/154031; ‘Bezemer) in view of Gunnoo et al. (‘Reviving old protecting group chemistry for site-selective peptide-protein conjugation’ ChemComm Communication v54 2018 pages 11929-11932; ‘Gunnoo’) in view of Cui et al. (US 2018/0079777; ‘Cui’) in view of Laidler et al. (US 2015/0110820; ‘Laidler’) in view of Mi et al. (CN 105504012 04-2016).
Mi et al. (CN 105504012 04-2016) is not in the English language. A copy of a translated version (Translation of CN 105504012 09-2014 Mi et al., 9 pages) is included and all references herein (unless otherwise specified) will be to the translated version (MiTranslation).
Bezemer teach methods for preparing AMG 416 (abstract) specifically the hydrocholoride salt of AMG 416 (section 0005). Bezemer teach in figure 2 the structure of the protected peptide on the resin specifically where Cys contains a Trt group and each Arg contains a Pbf group (section 0026 and figure 2 and claim 1). Bezemer teach deprotection with 2,2,2-trifluoroacetic acid (TFA) to result in a Cys modified product (figure 3 and figure 3 caption section 0027). Bezemer teach activating the side chain of the D-Cys residue (claim 1). Bezemer teach reaction with L-Cys to form a disulfide containing salt form (figure 4 and figure 4 caption sections 0014 and 0028). Bezemer teach that purification of the intermediate prior to conjugation with Cys can increase efficiency and decrease cost (section 0072). Bezemer teach the formation of the HCl salt form (figure 5 and figure 5 caption section 0029). Bezemer specifically recognizes a deprotection and cysteine activation step which includes water, TFA and TIPS (section 0066). Bezemer teach that the salt can be purified by HPLC (section 0068). Bezemer teach that the TFA salt can be converted to the hydrochloride salt by any means known in the art (section 0070). Bezemer teach carrying out a salt exchange procedure which are well known in the art (section 0007). Bezemer shows the use of HCl to convert to the HCl salt (figure 5). Bezemer teach that pharmaceutically acceptable salts include acetate (section 0044). Bezemer teach that the TFA salt may be converted to the pharmaceutically acceptable salt such as hydrochloride (section 0070). Bezemer teach purification by preparative chromatography (section 0097). Bezemer teach using HPLC to obtain fractions of the desired purity (section 0097).
Bezemer does not teach Scm as in claim 1b.
Gunnoo teach a simple strategy for conjugation using peptides with a Cys(Scm) protecting group which is described as efficient and site-selective and generally applicable for disulfide formation (abstract). Gunnoo teach an ease to introducing Cys(Scm) into peptides (last paragraph on page 11929) and specifically teach the use of the chloride form (scheme 2). Gunnoo teach the use of DTT to obtain a free thiol (page 11930 first complete paragraph). Gunnoo concludes that the Scm group can be used as an activating group for disulfide formation (page 11931 last paragraph).
Cui teach preparing etelcalcetide (abstract). Cui teach the use of hydrates and salts (section 0064) and specifically teach cysteine hydrochloride hydrate (section 0129). Cui teach that any suitable protecting group may be used to protect D-Cys (section 0104). Cui teach that the TFA salt (acetate salt) is converted to a pharmaceutically acceptable salt such as hydrocholoride salt (section 0006). Cui expressly refers to the 4HCl form (section 0108).
Laidler recognizes that the trifluoroacetate salt form of a peptide is not the most acceptable form and that acetate is considered to be a more acceptable form (sections 0008 and 0015). Laidler recognizes that acetic acid is a weaker acid than trifluoroacetic acid (section 0015).
MiTranslation teach the preparation of velcalcetide acetate peptide by using HPLC and acetic acid and acetonitrile (embodiment 12 connecting paragraph pages 7-8). Page number 3 (section 0003) of the untranslated Mi document shows the structure of velcalcetide.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Bezemer because Bezemer teach the synthesis of a specific compound with a disulfide and teach activating the side chain of the D-Cys residue (claim 1). Bezemer teach that purification of the intermediate prior to conjugation with Cys can increase efficiency and decrease cost (section 0072). Since Gunnoo teach a simple strategy for conjugation using peptides with a Cys(Scm) protecting group which is described as efficient and site-selective and generally applicable for disulfide formation (abstract) one would have been motivated to use the Scm group. Since Bezemer teach that pharmaceutically acceptable salts include acetate (section 0044) and teach that the salt may be converted to the pharmaceutically acceptable salt such as hydrochloride (section 0070) one would have been motivated to do such by using acetic acid for formation of the acetate. Further, Laidler recognizes that the trifluoroacetate salt form of a peptide is not the most acceptable form (sections 0008 and 0015) and MiTranslation teach the preparation of velcalcetide acetate peptide by using HPLC and acetic acid and acetonitrile (embodiment 12 connecting paragraph pages 7-8) (where velcalcetide is of the same sequence of etelcalcetide – see section 0003 on page 3 of the untranslated Mi document). Thus one would have been motivated to use known techniques to prepare the acetate form. Bezemer teach reaction with L-Cys to form a disulfide containing salt form (figure 4 and figure 4 caption sections 0014 and 0028) and Cui specifically teach cysteine hydrochloride hydrate (section 0129) for synthesis of the same peptide so one would have been motivated to use such form. One would have had a reasonable expectation of success since Cui teach that any suitable protecting group may be used to protect D-Cys (section 0104). Further, the other agents and steps were known.
In relation to formula II as recited in claim 1, Bezemer teach in figure 2 the structure of the protected peptide on the resin specifically where Cys contains a Trt group (section 0026 and figure 2 and claim 1).
In relation to step a of claim 1, Bezemer teach deprotection with 2,2,2-trifluoroacetic acid (TFA) to result in a Cys modified product (figure 3 and figure 3 caption section 0027).
In relation to step b of claim 1, Bezemer teach activating the side chain of D-Cys (claim 1). Gunnoo teach an ease to introducing Cys(Scm) into peptides (last paragraph on page 11929) and specifically teach the use of the chloride form (scheme 2). Bezemer specifically recognizes a deprotection and cysteine activation step which includes water, TFA and TIPS (section 0066).
In relation to step c of claim 1, MiTranslation teach the preparation of velcalcetide acetate peptide by using HPLC and acetic acid and acetonitrile (embodiment 12 connecting paragraph pages 7-8) (where velcalcetide is of the same sequence of etelcalcetide – see section 0003 on page 3 of the untranslated Mi document). Bezemer teach reaction with L-Cys to form a disulfide containing salt form (figure 4 and figure 4 caption sections 0014 and 0028). Bezemer teach the formation of the HCl salt form (figure 5 and figure 5 caption section 0029). Bezemer specifically recognizes a deprotection and cysteine activation step which includes water, TFA and TIPS (section 0066). Bezemer teach that the salt can be purified by HPLC (section 0068). Bezemer teach that pharmaceutically acceptable salts include acetate (section 0044).
In relation to step d of claim 1, Bezemer teach that the TFA salt may be converted to the pharmaceutically acceptable salt such as hydrochloride (section 0070). Cui expressly refers to the 4HCl form (section 0108). Bezemer teach that the TFA salt can be converted to the hydrochloride salt by any means known in the art (section 0070). Bezemer teach carrying out a salt exchange procedure which are well known in the art (section 0007). Bezemer shows the use of HCl to convert to the HCl salt (figure 5). Bezemer teach that pharmaceutically acceptable salts include acetate (section 0044). Bezemer teach that the TFA salt may be converted to the pharmaceutically acceptable salt such as hydrochloride (section 0070). Bezemer teach purification by preparative chromatography (section 0097). Bezemer teach using HPLC to obtain fractions of the desired purity (section 0097).
In relation to claim 2, Bezemer teach in figure 2 the structure of the protected peptide on the resin specifically where Cys contains a Trt group (section 0026 and figure 2 and claim 1). Further, Gunnoo teach a simple strategy for conjugation using peptides with a Cys(Scm) protecting group which is described as efficient and site-selective and generally applicable for disulfide formation (abstract) which utilizes an Acm group (scheme 2).
In relation to claims 3-5, Bezemer specifically recognizes a deprotection and cysteine activation step which includes water, TFA and TIPS (section 0066). Gunnoo teach the use of DTT to obtain a free thiol (page 11930 first complete paragraph).
In relation to claim 6, MiTranslation teach the preparation of velcalcetide acetate peptide by using HPLC and acetic acid and acetonitrile (embodiment 12 connecting paragraph pages 7-8) (where velcalcetide is of the same sequence of etelcalcetide – see section 0003 on page 3 of the untranslated Mi document). Bezemer teach HPLC purification using an acetate and acetonitrile (section 00100). Since Bezemer teach that pharmaceutically acceptable salts include acetate (section 0044) and teach that the salt may be converted to the pharmaceutically acceptable salt such as hydrochloride (section 0070) one would have been motivated to do such by using acetic acid for formation of the acetate.
In relation to claim 7, Bezemer teach reaction with L-Cys to form a disulfide containing salt form (figure 4 and figure 4 caption sections 0014 and 0028) and Cui specifically teach cysteine hydrochloride hydrate (section 0129).
Response to Arguments - 103
Applicant's arguments filed 12/21/25 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue that the claims require purification of a Scm-activated intermediate, Bezemer teach that purification of the intermediate prior to conjugation with Cys can increase efficiency and decrease cost (section 0072). Gunnoo teach a simple strategy for conjugation using peptides with a Cys(Scm) protecting group which is described as efficient and site-selective and generally applicable for disulfide formation (abstract). Gunnoo teach an ease to introducing Cys(Scm) into peptides (last paragraph on page 11929) and specifically teach the use of the chloride form (scheme 2). Gunnoo teach the use of DTT to obtain a free thiol (page 11930 first complete paragraph). Gunnoo concludes that the Scm group can be used as an activating group for disulfide formation (page 11931 last paragraph).
Although applicants argue that Bezemer teach away from the claimed invention, Bezemer teach that purification of the intermediate prior to conjugation with Cys can increase efficiency and decrease cost (section 0072). Thus, Bezemer does not teach purification solely of the final product as asserted by applicant.
Although applicants argue about the teachings of Bezemer alone, 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 about the teachings of Gunnoo or Cui or Laidler or Mi alone, 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 about a reasonable expectation of success, one would have had a reasonable expectation of success since Cui teach that any suitable protecting group may be used to protect D-Cys (section 0104). Further, the other agents and steps were known.
Although applicants argue about hindsight, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RONALD T NIEBAUER whose telephone number is (571)270-3059. The examiner can normally be reached M - F 6:30 - 2:30 EST.
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RONALD T. NIEBAUER
Primary Examiner
Art Unit 1658
/RONALD T NIEBAUER/Examiner, Art Unit 1658
Prosecution Insights