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 2/9/26 are acknowledged. Any objection or rejection from the 11/7/25 office action that is not addressed below is withdrawn based on the amendments.
Previously, Group 3 and the species of SEQ ID NO:3 were elected.
Claims 27-28 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/14/25.
Applicants state that claims 1-3, 5-7, 10, 13-19 and 23 read on the elected species. Claims 2 and 10 refer to a protecting group (or groups) for Thr. However, the elected sequence does not include a protecting group on Thr at position 5. In order to advance prosecution, claims 2 and 10 are included in the instant examination. Further, although the elected species as depicted in the reply contains E(tBu)-E(tBu) after the modified lysine at position 20, the sequences in the claims only contain a single E(tBu) at position 21 followed by F. The elected species has been interpreted such that position 22 is F.
The elected species shows ‘tBu’ for Asp and Glu. Since Asp and Gly include an oxygen atom on the side chain ‘OtBu’ and ‘tBu’ have been interpreted as being the same side chain protecting groups in the context of Asp and Glu. Any relevant art that was uncovered during the search for the elected species is cited herein in order to advance prosecution.
Claims 8-9 and 11-12 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/14/25.
Claims 4, 20-22, 24-26 and 29-35 have been canceled.
Claims 1-3, 5-7, 10, 13-19 and 23 are being examined.
Priority
The priority information is found in the filing receipt dated 4/6/23
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 1-3, 5-7, 10, 13-19 and 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 1 lines 5-7 refers to conjugation with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and then later refers to coupling with a compound that includes tBu protecting groups (claim 1 step ii). The claim language is unclear because in one location it appears to require a protected compound to be used in the conjugation/coupling step (see claim 1 step ii) but also refers to an unprotected compound (no tBu groups) in claim 1 lines 5-7. None of the dependent claims clarify the claim scope. As such, the scope of claim 1 and dependent claims is unclear. The claim has been interpreted as requiring ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H as part of the prepared compound.
Claim 1 section i refers to solid-phase and generically shows a circle on the right hand side of the formula which is described as ‘Fmoc amide resin’. Claim 1 section i refers to SEQ ID NO:2 and the sequence listing for SEQ ID NO:2 states that residue 34 is bound to Sieber resin. Claim 1 section ii refers to SEQ ID NO:5 and the sequence listing for SEQ ID NO:5 states that residue 34 is bound to Sieber resin. Claim 14 refers to a Sieber resin.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation Fmoc amide resin, and the claim also refers to SEQ ID NOs: 2 and 5 which recite Sieber resin which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. None of the dependent claims clarify the claim scope. It is unclear if claim 14 is a proper dependent claim.
Claim 19 generically shows a circle on the right hand side of the formula which is described as ‘Fmoc amide resin’. Claim 19 refers to SEQ ID NO: 17 and the sequence listing for SEQ ID NO: 17 states that residue 34 is bound to Sieber resin.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 19 recites the broad recitation Fmoc amide resin, and the claim also refers to SEQ ID NO: 17 which recite Sieber resin which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 23 generically shows a circle on the right hand side of the formula which is described as ‘Fmoc amide resin’. Claim 23 refers to SEQ ID NOs: 17 and 11 and the sequence listing for SEQ ID NOs: 17 and 11 state that the c-terminal residue is bound to Sieber resin.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 23 recites the broad recitation which is described as ‘Fmoc amide resin’, and the claim also refers to SEQ ID NOs: 17 and 11 which recite Sieber resin which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The claims have been given the broadest reasonable interpretation such that the Sieber resin is not required except for claim 14.
Response to Arguments - 112
Applicant's arguments filed 2/9/26 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.
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) 1-3, 5-7, 16-17, 19 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al. (US 2016/0368960; ‘Mezo’) in view of CN 109456401 (03-2019 as cited with IDS 12/6/22).
CN 109456401 (03-2019 as cited with IDS 12/6/22) is not in the English language. A translation of CN 109456401 (retrieved from https://patents.google.com/patent/CN109456401A/en on 10/30/25, 12 pages) is provided herein and all references will be to the translated version (‘CNtranslation’) unless otherwise specified.
Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract). In claim 12 and example 2 Mezo teach the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188). Mezo teach specific data (Table 3) for compound 2 (Tables 3-16). Mezo teach that compound 2 is synthesized as in example 1 except for 1 step that is different (section 0189). Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174) and Mtt on the lysine at position 20 (section 0175). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177). Mezo teach purification of the compound (sections 0177-0182).
Mezo does not teach the PG2 group as recited in claim 1 or the acylation in one step as recited in claim 1ii. Mezo does not teach the fragment condensation as in claims 19 and 23.
CNtranslation teach the semaglutide peptide and synthesis thereof (page 2 ‘Description’ section). CNtranslation teach that the side chain protecting group of Lys can be Mtt or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Mezo because Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract) and teach a specific compound (claim 12 and example 2) and provides specific data (Table 3) for compound 2 (Tables 3-16) showing beneficial properties. Thus, one would have been motivated to make such compound using methods and components known in the art. Mezo provides methods of synthesis in examples 1-2 including using an Fmoc Rink resin and standard side chain protecting groups including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Since CNtranslation teach a related peptide (page 2 ‘Description’ section) and teach synthesis methods that include advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines for example) one would have been motivated to incorporate the teachings of CNtranslation. CNtranslation teach that the side chain protecting group of Lys can be Mtt (as in Mezo) or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Based on the specific suggestion of CNtranslation one would have been motivated to use Dde as the protecting group on the side chain of Lys.
With respect to the conjugation to the side chain of Lys, CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2). Based on the advantages disclosed in CNtranslation one would have been motivated to couple the modified side chain group in a single step.
With respect to the peptide synthesis, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). Thus, one would have been motivated to use such approach with the compound taught by Mezo.
One would have had a reasonable expectation of success because the components as claimed were known and methods of synthesis were known (examples 1-2 of Mezo and embodiments of CNtranslation).
In relation to the compound prepared as recited in claim 1, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the solid phase synthesis and PG1 groups of claim 1i, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173) and teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174).
In relation to the PG2 group of claim 1i, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claim 1ii, Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (sections 0175-0176). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
In relation to claim 1iii-iv, Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177) followed by purification of the compound (sections 0177-0182).
In relation to claim 2, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Since Asp and Gly include an oxygen atom on the side chain ‘OtBu’ and ‘tBu’ have been interpreted as being the same side chain protecting groups in the context of Asp and Glu.
In relation to claim 3, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claims 5-7, CNtranslation teach that the side chain protecting group of Lys can be Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Although CNtranslation does not teach a specific amount of hydrazine hydrate, CNtranslation teach hydrazine hydrate for removal of Dde so one would have been motivated to optimize for such goal.
In relation to claims 16-17, Mezo teach purification of the compound (sections 0177-0182) and specifically recites RP-HPLC (section 0177).
In relation to the solid phase and resin of claim 19, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 19, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 19, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
In relation to the solid phase and resin of claim 23, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 23, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 23, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
Claim(s) 1-3, 5-7, 10, 13, 16-17, 19 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al. (US 2016/0368960; ‘Mezo’) in view of CN 109456401 (03-2019 as cited with IDS 12/6/22) in view of Reedtz-Runge et al. (US 2016/0143998; ‘Reedtz-Runge’).
CN 109456401 (03-2019 as cited with IDS 12/6/22) is not in the English language. A translation of CN 109456401 (retrieved from https://patents.google.com/patent/CN109456401A/en on 10/30/25, 12 pages) is provided herein and all references will be to the translated version (‘CNtranslation’) unless otherwise specified.
Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract). In claim 12 and example 2 Mezo teach the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188). Mezo teach specific data (Table 3) for compound 2 (Tables 3-16). Mezo teach that compound 2 is synthesized as in example 1 except for 1 step that is different (section 0189). Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174) and Mtt on the lysine at position 20 (section 0175). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177). Mezo teach purification of the compound (sections 0177-0182).
Mezo does not teach that PG2 is ivDde as in claim 10.
CNtranslation teach the semaglutide peptide and synthesis thereof (page 2 ‘Description’ section). CNtranslation teach that the side chain protecting group of Lys can be Mtt or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
Reedtz-Runge teach GLP-1 analogues (abstract). Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt or ivDde (section 0463).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Mezo because Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract) and teach a specific compound (claim 12 and example 2) and provides specific data (Table 3) for compound 2 (Tables 3-16) showing beneficial properties. Thus, one would have been motivated to make such compound using methods and components known in the art. Mezo provides methods of synthesis in examples 1-2 including using an Fmoc Rink resin and standard side chain protecting groups including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Since CNtranslation teach a related peptide (page 2 ‘Description’ section) and teach synthesis methods that include advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines for example) one would have been motivated to incorporate the teachings of CNtranslation. CNtranslation teach that the side chain protecting group of Lys can be Mtt (as in Mezo) or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Based on the specific suggestion of CNtranslation one would have been motivated to use Dde as the protecting group on the side chain of Lys. Since Reedtz-Runge teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Reedtz-Runge. Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt (as in Mezo) or ivDde (section 0463) so one would have been motivated to use the suggested ivDde group.
With respect to the conjugation to the side chain of Lys, CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2). Based on the advantages disclosed in CNtranslation one would have been motivated to couple the modified side chain group in a single step.
With respect to the peptide synthesis, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). Thus, one would have been motivated to use such approach with the compound taught by Mezo.
One would have had a reasonable expectation of success because the components as claimed were known and methods of synthesis were known (examples 1-2 of Mezo and embodiments of CNtranslation).
In relation to the compound prepared as recited in claim 1, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the solid phase synthesis and PG1 groups of claim 1i, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173) and teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174).
In relation to the PG2 group of claim 1i, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claim 1ii, Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (sections 0175-0176). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
In relation to claim 1iii-iv, Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177) followed by purification of the compound (sections 0177-0182).
In relation to claim 2, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Since Asp and Gly include an oxygen atom on the side chain ‘OtBu’ and ‘tBu’ have been interpreted as being the same side chain protecting groups in the context of Asp and Glu.
In relation to claim 3, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claims 5-7, CNtranslation teach that the side chain protecting group of Lys can be Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Although CNtranslation does not teach a specific amount of hydrazine hydrate, CNtranslation teach hydrazine hydrate for removal of Dde so one would have been motivated to optimize for such goal.
In relation to claim 10 and to the PG2 of the elected species, Reedtz-Runge teach that the epsilon amino group of lysine can be protected with ivDde (section 0463). Further, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG (sections 0184-0190) which corresponds to the residues as claimed. Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 and standard coupling (section 0174) as in claim 10.
In relation to claim 13, Mezo teach that an Fmoc Rink resin is used and the Fmoc groups were removed (section 0174).
In relation to claims 16-17, Mezo teach purification of the compound (sections 0177-0182) and specifically recites RP-HPLC (section 0177).
In relation to the solid phase and resin of claim 19, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 19, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 19, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
In relation to the solid phase and resin of claim 23, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 23, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 23, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
Claim(s) 1-3, 5-7, 10, 13-14, 16-17, 19 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al. (US 2016/0368960; ‘Mezo’) in view of CN 109456401 (03-2019 as cited with IDS 12/6/22) in view of Reedtz-Runge et al. (US 2016/0143998; ‘Reedtz-Runge’) in view of Werbitzky et al. (US 2013/0324699; ‘Werbitzky’).
Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract). In claim 12 and example 2 Mezo teach the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188). Mezo teach specific data (Table 3) for compound 2 (Tables 3-16). Mezo teach that compound 2 is synthesized as in example 1 except for 1 step that is different (section 0189). Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174) and Mtt on the lysine at position 20 (section 0175). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177). Mezo teach purification of the compound (sections 0177-0182).
Mezo does not teach specifically recite a Sieber resin as in claim 14.
CNtranslation teach the semaglutide peptide and synthesis thereof (page 2 ‘Description’ section). CNtranslation teach that the side chain protecting group of Lys can be Mtt or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
Reedtz-Runge teach GLP-1 analogues (abstract). Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt or ivDde (section 0463).
Werbitzky teach methods of synthesizing GLP-1 peptides (abstract and claims). Werbitzky recognizes Rink amide resins as well as a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038). Werbitzky recognize purification steps that include precipitation, filtration, rinsing and drying (section 0050).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Mezo because Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract) and teach a specific compound (claim 12 and example 2) and provides specific data (Table 3) for compound 2 (Tables 3-16) showing beneficial properties. Thus, one would have been motivated to make such compound using methods and components known in the art. Mezo provides methods of synthesis in examples 1-2 including using an Fmoc Rink resin and standard side chain protecting groups including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Since CNtranslation teach a related peptide (page 2 ‘Description’ section) and teach synthesis methods that include advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines for example) one would have been motivated to incorporate the teachings of CNtranslation. CNtranslation teach that the side chain protecting group of Lys can be Mtt (as in Mezo) or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Based on the specific suggestion of CNtranslation one would have been motivated to use Dde as the protecting group on the side chain of Lys. Since Reedtz-Runge teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Reedtz-Runge. Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt (as in Mezo) or ivDde (section 0463) so one would have been motivated to use the suggested ivDde group. Since Werbitzky teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Werbitzky. Werbitzky recognizes Rink amide resins (as in Mezo) as well as a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038) so one would have been motivated to use the Sieber resin.
With respect to the conjugation to the side chain of Lys, CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2). Based on the advantages disclosed in CNtranslation one would have been motivated to couple the modified side chain group in a single step.
With respect to the peptide synthesis, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). Thus, one would have been motivated to use such approach with the compound taught by Mezo.
One would have had a reasonable expectation of success because the components as claimed were known and methods of synthesis were known (examples 1-2 of Mezo and embodiments of CNtranslation).
In relation to the compound prepared as recited in claim 1, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the solid phase synthesis and PG1 groups of claim 1i, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173) and teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174).
In relation to the PG2 group of claim 1i, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claim 1ii, Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (sections 0175-0176). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
In relation to claim 1iii-iv, Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177) followed by purification of the compound (sections 0177-0182).
In relation to claim 2, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Since Asp and Gly include an oxygen atom on the side chain ‘OtBu’ and ‘tBu’ have been interpreted as being the same side chain protecting groups in the context of Asp and Glu.
In relation to claim 3, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claims 5-7, CNtranslation teach that the side chain protecting group of Lys can be Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Although CNtranslation does not teach a specific amount of hydrazine hydrate, CNtranslation teach hydrazine hydrate for removal of Dde so one would have been motivated to optimize for such goal.
In relation to claim 10 and to the PG2 of the elected species, Reedtz-Runge teach that the epsilon amino group of lysine can be protected with ivDde (section 0463). Further, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG (sections 0184-0190) which corresponds to the residues as claimed. Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 and standard coupling (section 0174) as in claim 10.
In relation to claim 13, Mezo teach that an Fmoc Rink resin is used and the Fmoc groups were removed (section 0174).
In relation to claim 14, Werbitzky teach a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038).
In relation to claims 16-17, Mezo teach purification of the compound (sections 0177-0182) and specifically recites RP-HPLC (section 0177).
In relation to the solid phase and resin of claim 19, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 19, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 19, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
In relation to the solid phase and resin of claim 23, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 23, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 23, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
Claim(s) 1-3, 5-7, 10, 13-15, 16-17, 19 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al. (US 2016/0368960; ‘Mezo’) in view of CN 109456401 (03-2019 as cited with IDS 12/6/22) in view of Reedtz-Runge et al. (US 2016/0143998; ‘Reedtz-Runge’) in view of Werbitzky et al. (US 2013/0324699; ‘Werbitzky’) in view of Eisenhuth et al. (WO 2019/149723; ‘Eisenhuth’).
Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract). In claim 12 and example 2 Mezo teach the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188). Mezo teach specific data (Table 3) for compound 2 (Tables 3-16). Mezo teach that compound 2 is synthesized as in example 1 except for 1 step that is different (section 0189). Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174) and Mtt on the lysine at position 20 (section 0175). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177). Mezo teach purification of the compound (sections 0177-0182).
Mezo does not teach that the specifics of claim 15.
CNtranslation teach the semaglutide peptide and synthesis thereof (page 2 ‘Description’ section). CNtranslation teach that the side chain protecting group of Lys can be Mtt or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
Reedtz-Runge teach GLP-1 analogues (abstract). Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt or ivDde (section 0463).
Werbitzky teach methods of synthesizing GLP-1 peptides (abstract and claims). Werbitzky recognizes Rink amide resins as well as a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038). Werbitzky recognize purification steps that include precipitation, filtration, rinsing and drying (section 0050).
Eisenhuth teach manufacture of glucagon peptides (abstract and claims). Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7). Eisenhuth recognizes stirring during pH adjustments for example (page 34 first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Mezo because Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract) and teach a specific compound (claim 12 and example 2) and provides specific data (Table 3) for compound 2 (Tables 3-16) showing beneficial properties. Thus, one would have been motivated to make such compound using methods and components known in the art. Mezo provides methods of synthesis in examples 1-2 including using an Fmoc Rink resin and standard side chain protecting groups including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Since CNtranslation teach a related peptide (page 2 ‘Description’ section) and teach synthesis methods that include advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines for example) one would have been motivated to incorporate the teachings of CNtranslation. CNtranslation teach that the side chain protecting group of Lys can be Mtt (as in Mezo) or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Based on the specific suggestion of CNtranslation one would have been motivated to use Dde as the protecting group on the side chain of Lys. Since Reedtz-Runge teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Reedtz-Runge. Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt (as in Mezo) or ivDde (section 0463) so one would have been motivated to use the suggested ivDde group. Since Werbitzky teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Werbitzky. Werbitzky recognizes Rink amide resins (as in Mezo) as well as a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038) so one would have been motivated to use the Sieber resin. Since Eisenhuth teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Eisenhuth. Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7) and recognizes stirring during pH adjustments for example (page 34 first paragraph) so one would have been motivated to carry out such steps.
With respect to the conjugation to the side chain of Lys, CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2). Based on the advantages disclosed in CNtranslation one would have been motivated to couple the modified side chain group in a single step.
With respect to the peptide synthesis, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). Thus, one would have been motivated to use such approach with the compound taught by Mezo.
One would have had a reasonable expectation of success because the components as claimed were known and methods of synthesis were known (examples 1-2 of Mezo and embodiments of CNtranslation).
In relation to the compound prepared as recited in claim 1, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the solid phase synthesis and PG1 groups of claim 1i, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173) and teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174).
In relation to the PG2 group of claim 1i, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claim 1ii, Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (sections 0175-0176). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
In relation to claim 1iii-iv, Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177) followed by purification of the compound (sections 0177-0182).
In relation to claim 2, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Since Asp and Gly include an oxygen atom on the side chain ‘OtBu’ and ‘tBu’ have been interpreted as being the same side chain protecting groups in the context of Asp and Glu.
In relation to claim 3, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claims 5-7, CNtranslation teach that the side chain protecting group of Lys can be Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Although CNtranslation does not teach a specific amount of hydrazine hydrate, CNtranslation teach hydrazine hydrate for removal of Dde so one would have been motivated to optimize for such goal.
In relation to claim 10 and to the PG2 of the elected species, Reedtz-Runge teach that the epsilon amino group of lysine can be protected with ivDde (section 0463). Further, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG (sections 0184-0190) which corresponds to the residues as claimed. Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 and standard coupling (section 0174) as in claim 10.
In relation to claim 13, Mezo teach that an Fmoc Rink resin is used and the Fmoc groups were removed (section 0174).
In relation to claim 14, Werbitzky teach a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038).
In relation to claim 15, Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7) and recognizes stirring during pH adjustments for example (page 34 first paragraph).
In relation to claims 16-17, Mezo teach purification of the compound (sections 0177-0182) and specifically recites RP-HPLC (section 0177).
In relation to the solid phase and resin of claim 19, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 19, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 19, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
In relation to the solid phase and resin of claim 23, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 23, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 23, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
Claim(s) 1-3, 5-7, 10, 13-19 and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al. (US 2016/0368960; ‘Mezo’) in view of CN 109456401 (03-2019 as cited with IDS 12/6/22) in view of Reedtz-Runge et al. (US 2016/0143998; ‘Reedtz-Runge’) in view of Werbitzky et al. (US 2013/0324699; ‘Werbitzky’) in view of Eisenhuth et al. (WO 2019/149723; ‘Eisenhuth’) in view of Quay et al. (US 2008/0318837; ‘Quay’).
Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract). In claim 12 and example 2 Mezo teach the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188). Mezo teach specific data (Table 3) for compound 2 (Tables 3-16). Mezo teach that compound 2 is synthesized as in example 1 except for 1 step that is different (section 0189). Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174) and Mtt on the lysine at position 20 (section 0175). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177). Mezo teach purification of the compound (sections 0177-0182).
Mezo does not teach that the specifics of claim 18.
CNtranslation teach the semaglutide peptide and synthesis thereof (page 2 ‘Description’ section). CNtranslation teach that the side chain protecting group of Lys can be Mtt or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
Reedtz-Runge teach GLP-1 analogues (abstract). Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt or ivDde (section 0463).
Werbitzky teach methods of synthesizing GLP-1 peptides (abstract and claims). Werbitzky recognizes Rink amide resins as well as a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038). Werbitzky recognize purification steps that include precipitation, filtration, rinsing and drying (section 0050).
Eisenhuth teach manufacture of glucagon peptides (abstract and claims). Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7). Eisenhuth recognizes stirring during pH adjustments for example (page 34 first paragraph).
Quay teach peptides including GLP-1 peptides (section 0001). Quay teach that GLP-1 also includes salts (section 0048) and that peptides also include salts (section 0074). Quay teach sodium salts as effective for delivery of the agent (section 0187). Quay specifically recites sodium hydroxide (sections 0197 and 0205). Werbitzky recognize purification steps that include precipitation, filtration, rinsing and drying (section 0050).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Mezo because Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract) and teach a specific compound (claim 12 and example 2) and provides specific data (Table 3) for compound 2 (Tables 3-16) showing beneficial properties. Thus, one would have been motivated to make such compound using methods and components known in the art. Mezo provides methods of synthesis in examples 1-2 including using an Fmoc Rink resin and standard side chain protecting groups including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Since CNtranslation teach a related peptide (page 2 ‘Description’ section) and teach synthesis methods that include advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines for example) one would have been motivated to incorporate the teachings of CNtranslation. CNtranslation teach that the side chain protecting group of Lys can be Mtt (as in Mezo) or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Based on the specific suggestion of CNtranslation one would have been motivated to use Dde as the protecting group on the side chain of Lys. Since Reedtz-Runge teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Reedtz-Runge. Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt (as in Mezo) or ivDde (section 0463) so one would have been motivated to use the suggested ivDde group. Since Werbitzky teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Werbitzky. Werbitzky recognizes Rink amide resins (as in Mezo) as well as a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038) so one would have been motivated to use the Sieber resin. Since Eisenhuth teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Eisenhuth. Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7) and recognizes stirring during pH adjustments for example (page 34 first paragraph) so one would have been motivated to carry out such steps. Since Quay teach related peptides (section 0001) one would have been motivated to incorporate the teachings of Quay. Quay teach that GLP-1 also includes salts (section 0048) and that peptides also include salts (section 0074). Quay teach sodium salts as effective for delivery of the agent (section 0187). Quay specifically recites sodium hydroxide (sections 0197 and 0205) so one would have been motivated to carry out such steps using the known methods taught by Werbitzky (section 0050).
With respect to the conjugation to the side chain of Lys, CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2). Based on the advantages disclosed in CNtranslation one would have been motivated to couple the modified side chain group in a single step.
With respect to the peptide synthesis, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). Thus, one would have been motivated to use such approach with the compound taught by Mezo.
One would have had a reasonable expectation of success because the components as claimed were known and methods of synthesis were known (examples 1-2 of Mezo and embodiments of CNtranslation).
In relation to the compound prepared as recited in claim 1, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the solid phase synthesis and PG1 groups of claim 1i, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173) and teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174).
In relation to the PG2 group of claim 1i, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claim 1ii, Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (sections 0175-0176). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
In relation to claim 1iii-iv, Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177) followed by purification of the compound (sections 0177-0182).
In relation to claim 2, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Since Asp and Gly include an oxygen atom on the side chain ‘OtBu’ and ‘tBu’ have been interpreted as being the same side chain protecting groups in the context of Asp and Glu.
In relation to claim 3, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claims 5-7, CNtranslation teach that the side chain protecting group of Lys can be Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Although CNtranslation does not teach a specific amount of hydrazine hydrate, CNtranslation teach hydrazine hydrate for removal of Dde so one would have been motivated to optimize for such goal.
In relation to claim 10 and to the PG2 of the elected species, Reedtz-Runge teach that the epsilon amino group of lysine can be protected with ivDde (section 0463). Further, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG (sections 0184-0190) which corresponds to the residues as claimed. Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 and standard coupling (section 0174) as in claim 10.
In relation to claim 13, Mezo teach that an Fmoc Rink resin is used and the Fmoc groups were removed (section 0174).
In relation to claim 14, Werbitzky teach a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038).
In relation to claim 15, Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7) and recognizes stirring during pH adjustments for example (page 34 first paragraph).
In relation to claims 16-17, Mezo teach purification of the compound (sections 0177-0182) and specifically recites RP-HPLC (section 0177).
In relation to claim 18, Quay teach that GLP-1 also includes salts (section 0048) and that peptides also include salts (section 0074). Quay teach sodium salts as effective for delivery of the agent (section 0187). Quay specifically recites sodium hydroxide (sections 0197 and 0205) so one would have been motivated to carry out such steps using the known methods taught by Werbitzky (section 0050). Werbitzky recognize purification steps that include precipitation, filtration, rinsing and drying (section 0050).
In relation to the solid phase and resin of claim 19, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 19, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 19, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
In relation to the solid phase and resin of claim 23, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 23, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 23, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
Response to Arguments – 103
Applicant's arguments filed 2/9/26 have been fully considered but they are not persuasive with respect to the rejections set forth above.
Although applicants refer to hindsight reasoning and refer to a motivation of advantages, preferences and conveniences, 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). MPEP 2143.01 refers to modifying the teachings of a reference based on some teaching, suggestion or motivation to do so. The fact that applicants themselves refer to advantages, preferences and conveniences is a recognition of various motivations to modify the prior art teaching.
Although applicants argue that the proposed modifications are not explained, it is first noted that the office action of 11/7/25 is 55 pages in length and includes specific details. For example, the office action states: “CNtranslation teach that the side chain protecting group of Lys can be Mtt (as in Mezo) or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Based on the specific suggestion of CNtranslation one would have been motivated to use Dde as the protecting group on the side chain of Lys.”
Although applicants argue that a skilled artisan would not substitute or modify as claimed, MPEP 2141 expressly recognizes a rationale to support a rejection under 35 USC 103 as “Simple substitution of one known element for another to obtain predictable results” and MPEP 2143 provides specific examples. MPEP 2143 expressly states: “the rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art”.
With respect to the skilled artisan, MPEP 2141.03 recognizes that a person of ordinary skill in the art is a person of ordinary creativity not an automaton and will be able to fit the teachings of multiple references together like pieces of a puzzle. MPEP 2141.03 states that “Office personnel may also take into account the inferences and creative steps that a person of ordinary skill in the art would employ.”
Although applicants argue that the teachings of CNtranslation are not mapped onto steps of the claim, the office action states: “CNtranslation teach that the side chain protecting group of Lys can be Mtt (as in Mezo) or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Based on the specific suggestion of CNtranslation one would have been motivated to use Dde as the protecting group on the side chain of Lys.”
Although applicants argue that Reedtz-Runge does not teach replacing Mezo’s strategy, 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). Reedtz-Runge is not even used in the first 103 rejection that includes claims 1, 19 and 23. As set forth in the office action, Reedtz-Runge provides teachings about protecting groups for lysine (section 0463).
Although applicants argue that Werbitzky does not teach all the claimed steps, 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). Werbitzky is not even used in the first 103 rejection that includes claims 1, 19 and 23. As set forth in the office action, Werbitzky provides teachings related to known preferred resins (section 0038).
Although applicants argue that Eisenhuth and Quay do not teach all the claimed steps, 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). Eisenhuth and Quay are not even used in the first 103 rejection that includes claims 1, 19 and 23. As set forth in the office action, Eisenhuth and Quay provides teachings related to purification conditions.
Although applicants argue that Mezo refer to successive couplings, MPEP 2123 recognizes that the mere disclosure of more than one alternative does not constitute a teaching away.
Although applicants acknowledge teachings in the art they argue that one would not have made those selections, MPEP 2141.03 recognizes that a person of ordinary skill in the art is a person of ordinary creativity not an automaton and will be able to fit the teachings of multiple references together like pieces of a puzzle. MPEP 2141.03 states that “Office personnel may also take into account the inferences and creative steps that a person of ordinary skill in the art would employ.”
Double Patenting
Claims were previously rejected under Double Patenting. Since the claims have been amended the rejection is updated to correspond to the instant claims.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-7, 10, 13-19 and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,938,335 (‘335’ as cited with IDS 12/6/22) in view of Mezo et al. (US 2016/0368960; ‘Mezo’) in view of CN 109456401 (03-2019 as cited with IDS 12/6/22) in view of Reedtz-Runge et al. (US 2016/0143998; ‘Reedtz-Runge’) in view of Werbitzky et al. (US 2013/0324699; ‘Werbitzky’) in view of Eisenhuth et al. (WO 2019/149723; ‘Eisenhuth’) in view of Quay et al. (US 2008/0318837; ‘Quay’).
335 recites a specific compound or a salt thereof (claim 12). 335 recites a process for manufacturing of the compound (claim 20).
335 does not recite all of the processing steps as claimed.
Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract). In claim 12 and example 2 Mezo teach the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188). Mezo teach specific data (Table 3) for compound 2 (Tables 3-16). Mezo teach that compound 2 is synthesized as in example 1 except for 1 step that is different (section 0189). Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174) and Mtt on the lysine at position 20 (section 0175). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177). Mezo teach purification of the compound (sections 0177-0182).
CNtranslation teach the semaglutide peptide and synthesis thereof (page 2 ‘Description’ section). CNtranslation teach that the side chain protecting group of Lys can be Mtt or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
Reedtz-Runge teach GLP-1 analogues (abstract). Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt or ivDde (section 0463).
Werbitzky teach methods of synthesizing GLP-1 peptides (abstract and claims). Werbitzky recognizes Rink amide resins as well as a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038). Werbitzky recognize purification steps that include precipitation, filtration, rinsing and drying (section 0050).
Eisenhuth teach manufacture of glucagon peptides (abstract and claims). Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7). Eisenhuth recognizes stirring during pH adjustments for example (page 34 first paragraph).
Quay teach peptides including GLP-1 peptides (section 0001). Quay teach that GLP-1 also includes salts (section 0048) and that peptides also include salts (section 0074). Quay teach sodium salts as effective for delivery of the agent (section 0187). Quay specifically recites sodium hydroxide (sections 0197 and 0205). Werbitzky recognize purification steps that include precipitation, filtration, rinsing and drying (section 0050).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of 335 because 335 expressly teach manufacturing a specific compound (claims 20 and 12). One would have been motivated to manufacture using known steps. Mezo teach glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes and obesity (abstract) and teach a specific compound (claim 12 and example 2) and provides specific data (Table 3) for compound 2 (Tables 3-16) showing beneficial properties which is the same as the compound of claim 12 of 335. Thus, one would have been motivated to make such compound using methods and components known in the art. Mezo provides methods of synthesis in examples 1-2 including using an Fmoc Rink resin and standard side chain protecting groups including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (section 0175). Mezo teach that successive couplings were used to modify the lysine at position 20 (section 0176). Since CNtranslation teach a related peptide (page 2 ‘Description’ section) and teach synthesis methods that include advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines for example) one would have been motivated to incorporate the teachings of CNtranslation. CNtranslation teach that the side chain protecting group of Lys can be Mtt (as in Mezo) or Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Based on the specific suggestion of CNtranslation one would have been motivated to use Dde as the protecting group on the side chain of Lys. Since Reedtz-Runge teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Reedtz-Runge. Reedtz-Runge teach that the epsilon amino group of lysine can be protected with either Mtt (as in Mezo) or ivDde (section 0463) so one would have been motivated to use the suggested ivDde group. Since Werbitzky teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Werbitzky. Werbitzky recognizes Rink amide resins (as in Mezo) as well as a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038) so one would have been motivated to use the Sieber resin. Since Eisenhuth teach related peptides (abstract and claims) one would have been motivated to incorporate the teachings of Eisenhuth. Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7) and recognizes stirring during pH adjustments for example (page 34 first paragraph) so one would have been motivated to carry out such steps. Since Quay teach related peptides (section 0001) one would have been motivated to incorporate the teachings of Quay. Quay teach that GLP-1 also includes salts (section 0048) and that peptides also include salts (section 0074). Quay teach sodium salts as effective for delivery of the agent (section 0187). Quay specifically recites sodium hydroxide (sections 0197 and 0205) so one would have been motivated to carry out such steps using the known methods taught by Werbitzky (section 0050).
With respect to the conjugation to the side chain of Lys, CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2). Based on the advantages disclosed in CNtranslation one would have been motivated to couple the modified side chain group in a single step.
With respect to the peptide synthesis, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides and pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). Thus, one would have been motivated to use such approach with the compound taught by Mezo.
One would have had a reasonable expectation of success because the components as claimed were known and methods of synthesis were known (examples 1-2 of Mezo and embodiments of CNtranslation).
In relation to the compound prepared as recited in claim 1, 335 recites a specific compound (claim 12). Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the solid phase synthesis and PG1 groups of claim 1i, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173) and teach that an Fmoc Rink resin is used and that standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174).
In relation to the PG2 group of claim 1i, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claim 1ii, Mezo teach that after completion of the synthesis of the linear peptide that the protecting group on the lysine at position 20 was selectively removed to make it available for further reaction (sections 0175-0176). CNtranslation teach the use of condensation of the modified side chain using for example HO-AEEA-AEEA-rGlu(OtBu)-Oct-(OtBu) (page 5 section 3.2 and page 7 section 3.2 and page 8 section 3.2).
In relation to claim 1iii-iv, Mezo teach that the peptide is removed from the support and side chain protecting groups are removed (section 0177) followed by purification of the compound (sections 0177-0182).
In relation to claim 2, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). Since Asp and Gly include an oxygen atom on the side chain ‘OtBu’ and ‘tBu’ have been interpreted as being the same side chain protecting groups in the context of Asp and Glu.
In relation to claim 3, CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to claims 5-7, CNtranslation teach that the side chain protecting group of Lys can be Dde and when Dde is used the protecting group is removed with a combination of hydrazine hydrate and DMF (claim 8 on page 2 and page 4 lines 6-9). Although CNtranslation does not teach a specific amount of hydrazine hydrate, CNtranslation teach hydrazine hydrate for removal of Dde so one would have been motivated to optimize for such goal.
In relation to claim 10 and to the PG2 of the elected species, Reedtz-Runge teach that the epsilon amino group of lysine can be protected with ivDde (section 0463). Further, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG (sections 0184-0190) which corresponds to the residues as claimed. Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 and standard coupling (section 0174) as in claim 10.
In relation to claim 13, Mezo teach that an Fmoc Rink resin is used and the Fmoc groups were removed (section 0174).
In relation to claim 14, Werbitzky teach a Sieber resin and specifically states that the Sieber resin as among the most preferred (section 0038).
In relation to claim 15, Eisenhuth teach advantages in purity by subjecting the peptide to a pH treatment of 7.2 and additionally a pH treatment of 2.0 for example for time periods including hours (pages 29 line 30-page 30 line 7) and recognizes stirring during pH adjustments for example (page 34 first paragraph).
In relation to claims 16-17, Mezo teach purification of the compound (sections 0177-0182) and specifically recites RP-HPLC (section 0177).
In relation to claim 18, Quay teach that GLP-1 also includes salts (section 0048) and that peptides also include salts (section 0074). Quay teach sodium salts as effective for delivery of the agent (section 0187). Quay specifically recites sodium hydroxide (sections 0197 and 0205) so one would have been motivated to carry out such steps using the known methods taught by Werbitzky (section 0050). Werbitzky recognize purification steps that include precipitation, filtration, rinsing and drying (section 0050).
In relation to the solid phase and resin of claim 19, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 19, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 19, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include pentapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
In relation to the solid phase and resin of claim 23, Mezo teach in example 1 that the synthesis is solid-phase synthesis (section 0173). Mezo teach that an Fmoc Rink resin is used (section 0174).
In relation to the amino acid sequence of claim 23, Mezo teach in claim 12 and example 2 the compound H(Aib)QGTFTSDYSKYLDEKKAKEFVEWLLEGGPSSG where K at position 20 is modified at the epsilon amino group of the K with ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(gamma-Glu)-CO-(CH2)18CO2H and the C-terminal amino acid is amidated as a C-terminal primary amide (sections 0184-0190) which is called compound 2 (section 0188).
In relation to the protecting groups of claim 23, Mezo teach standard side chain protecting groups are used including Boc for Trp and Lys; OtBu for Asp and Glu; tBu for Ser, Thr and Tyr; Trt for Gln; and di-Boc for His at position 1 (section 0174). CNtranslation teach that the side chain protecting group of Lys can be Dde (claim 8 on page 2 and page 4 lines 6-9).
In relation to the coupling and fragment of claim 19, CNtranslation teach the use of peptide fragments during the synthesis with advantages in time, cost, efficiency, purification and less waste (page 3 first 11 lines) and recites a variety of fragments that include tetrapeptides (page 3 lines 12-21) and teach that the fragment condensation leads to improved purity and yield (page 3 lines 19-21). When applying such strategy to the compound of Mezo the resulting compounds are as in claim 19.
Response to Arguments – Double Patenting
Applicant's arguments filed 2/9/26 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue that external prior art is used in the rejection, MPEP 804 II B 3 states: “In view of the similarities, the factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966) that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 should be considered when making a nonstatutory double patenting analysis based on "obviousness." ” and further refers to the use of secondary references. Thus the use of secondary references is proper.
Although applicants argue about individual teachings of references, the double patenting rejection is based on a particular patent and additional references. 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 same defects as set forth with respect to the 103 rejections, such arguments are addressed above and not found persuasive.
Although applicants argue that they are willing to consider a terminal disclaimer, no terminal disclaimer is of record. A consideration or a willingness to consider is not the equivalent of filing a terminal disclaimer.
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
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