DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. 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 for the cited rejections 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.
3. Response to Election/Restriction filed on 1/10/2023 is acknowledged.
4. Claim filed on 7/28/2021 is acknowledged.
5. Claims 14 and 30-35 have been cancelled.
6. Claims 1-13, 15-29 and 36-38 are pending in this application.
7. Claims 36-38 are withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claims 2, 4, 10-13 and 18-25 are further withdrawn from consideration as being drawn to non-elected species.
8. Claims 1, 3, 5-9, 15-17 and 26-29 are under examination.
Priority
9. The instant application is a continuation of US Application No. 17/166596 filed on 2/3/2021, which is a continuation of US Application No. 16/083201 filed on 9/7/2018, which is a 371 of PCT/US17/021999 filed on 3/13/2017, which claims the benefit of US Provisional Application No. 62/310145 filed on 3/18/2016. US Provisional Application No. 62/310145 provides support to the compound recited in instant claims 1, 3, 5-9, 17 and 29. However, US Provisional Application No. 62/310145 fails to disclose all of instant claimed PEP and/or CON recited in instant claims 15, 16 and 26-28. Therefore, the priority claim has been found invalid for instant claims 15, 16 and 26-28. Thus, the effective filing date of instant claims 1, 3, 5-9, 17 and 29 is the filing date of US Provisional Application No. 62/310145, which is 3/18/2016; and the effective filing date of instant claims 15, 16 and 26-28 is the filing date of PCT/US17/021999, which is 3/13/2017.
Elections/Restrictions
10. Applicant’s election of Group 1 (claims 1-13 and 15-29) and election of CON4 as species of compound in the reply filed on 1/10/2023 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). The requirement is made FINAL in this office action.
Group 1 is drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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; a compound comprising a conjugate selected from the group consisting of CON1-CON22, CON24-CON53 and CON55-CON161; a compound comprising the formula A-LM-B, wherein A is human insulin molecule or human insulin analog molecule; B is a incretin molecule or glucagon peptide modified to have agonist activity at the GLP1 receptor, agonist activity at the GIP receptor, agonist the GLP1 and GCG receptors, or agonist activity at the GLP-1 and GIP receptors; and LM is a linking moiety; a compound comprising an insulin analog selected from the group consisting of INS1-INS31 conjugated to a peptide selected from the group consisting of PEP1-PEP132; a compound comprising a conjugate selected from the group consisting of CON1-CON22, CON24-CON53, CON55-CON99, and CON101-CON161; and a pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable carrier. A search was conducted on the elected species; and prior art was found. Claims 2, 4, 10-13 and 18-25 are further withdrawn from consideration as being drawn to non-elected species. Claims 1, 3, 5-9, 15-17 and 26-29 are examined on the merits in this office action.
Claim Interpretations
11. With regards to the formula
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recited in instant claims 1 and 17, in the instant case, in view of the disclosure of instant specification, in particular Table 3 in instant specification, for the purpose of this examination, the Examiner is interpreting the R1 and R2 groups broadly include the part of the amino acid, such as side chain, in both the insulin molecule and the peptide that are used to connect to the linking moiety.
12. With regards to INS1-INS32 and CONs comprising such INS recited in instant claims, based on the disclosure of instant specification, in particular, page 68, lines 8-19 and the working examples in instant specification, the Examiner is interpreting the insulin in INS1-INS32 is recombinant human insulin or analog thereof with the structure
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, wherein the insulin is a heterodimer.
Objections
13. The specification is objected to for the following minor informality: The specification recites “1,2-disubstituted 1,2,3-triazole” on page 12, lines 7, 13 and 19; and many others throughout the specification. There appears to be an error in this recitation. The recitation should be “1,4-disubstituted 1,2,3-triazole”. Applicant is required to correct this error.
14. The specification is objected to for the following minor informality: The specification recites the amino acid sequence of SEQ ID NO: 59, 69, 93, 94, 136, 140 and 163 in Table 1 of instant specification. However, each of these amino acid sequences is inconsistent with the corresponding SEQ ID NO in the sequence listing filed on 7/28/2021. For SEQ ID NO: 59 or 163, in the filed sequence listing, the amino acid at position 21 is Asp. However, the MISC_FEATURE section states Xaa21 is Nle(epsilon-N3). For SEQ ID NO: 69, in the filed sequence listing, the amino acid at position 22 is Xaa, which is not specified. For SEQ ID NO: 93, 94, 136 or 140, in the filed sequence listing, the amino acid at positions 30 and 31 are Lys Xaa; and the MISC_FEATURE section states Xaa30 is Nle(epsilon-N3), and Xaa31 is gamma-Glu. Applicant is required to correct these errors.
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
15. The drawings are objected to for the following minor informality:
Figure 2D: the description for Figure 2D is missing.
Figures 2A and 3: these figures appear to be incomplete. The name of last compound in each of these figures is missing.
In the instant case, based on the disclosure of US Provisional Application No. 62/310145, it appears the last compound in Figure 2A is CON17; and the last compound in Figure 3 is CON79.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
16. Claims 1 and 17 are objected to for the following minor informality: Applicant is suggested to amend claims 1 and 17 as followings: (a) add a comma after the recites formula or formulae, as an example, “
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,”; (b) amend the recited “n is 1-50” and “n is independently 1-50” as “n is an integer selected from 1-50” and “n is an integer independently selected from 1-50”; (c) incorporate the chemical formula and/or structure of each of the recited “(PEG2)n”, “(PEG2)n-(γGlu)p-Cn”, “(PEG2)n-Cn”, “(PEG)n(PEG)n”, “PEGn-(Lys-(γGlu)pCn)-Cn”, and “C5- Lys(γE-Cn)-PEGn” from the specification into these claims; (d) amend the recited “the incretin peptide” in claim 1 as “the peptide”; (e) amend the recited “…lines with the proviso…” as “…lines, with the proviso…; and (f) amend the recited “1,4-disubstitued 1,2,3-triazole” recited in claim 17 as “1,4-disubstituted 1,2,3-triazole”.
17. Claim 3 is objected to for the following minor informality: Applicant is suggested to amended claim 3 as "…(a) an azido-norleucine, and the insulin molecule comprises a linker arm having a proximal end linked to the amino group of an amino acid of the insulin molecule and a distal end linked to an alkynyl group, wherein the azido group and the alkynyl group form the 1,4-disubstituted 1,2,3-triazole; or (b) an alkynyl- norleucine, and the insulin molecule comprises a linker arm having a proximal end linked to the amino group of an amino acid of the insulin molecule and a distal end linked to an azido group, wherein the azido group and the alkynyl group form the 1,4-disubstituted 1,2,3- triazole; or (c) a propargyl-glycine, and the insulin molecule comprises a linker arm having a proximal end linked to the amino group of an amino acid of the insulin molecule and a distal end linked to an azido group, wherein the azido group and the propargyl group form the 1,4-disubstituted 1,2,3-triazole".
18. Claim 15 is objected to for the following minor informality: Applicant is suggested to amended claim 15 as "…wherein the compound comprises a peptide selected from the group consisting of PEP1 to PEP132".
19. Claim 16 is objected to for the following minor informality: Applicant is suggested to amended claim 16 as “A compound comprising a conjugate selected from the group consisting of: CON1… ".
20. Claim 29 is objected to for the following minor informality: Applicant is suggested to amended “Claim 1” recited in claim 29 as "claim 1".
Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (b)
21. 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.
22. Claims 15, 16 and 26-28 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 pre-AIA the applicant regards as the invention.
23. Claims 15, 16 and 26-28 recite either PEP25 of SEQ ID NO: 59, PEP35 of SEQ ID NO: 69, PEP59 of SEQ ID NO: 93, PEP60 of SEQ ID NO: 94, PEP102 of SEQ ID NO: 136, PEP106 of SEQ ID NO: 140, and PEP129 of SEQ ID NO: 163; and/or CONs comprising such PEPs, which are CON50, CON76, CON131, CON135 and CON158.
However, each of these amino acid sequences recited in Table 1 of instant specification is inconsistent with the corresponding SEQ ID NO in the sequence listing filed on 7/28/2021. For SEQ ID NO: 59 or 163, in the filed sequence listing, the amino acid at position 21 is Asp. However, the MISC_FEATURE section states Xaa21 is Nle(epsilon-N3). For SEQ ID NO: 69, in the filed sequence listing, the amino acid at position 22 is Xaa, which is not specified. For SEQ ID NO: 93, 94, 136 or 140, in the filed sequence listing, the amino acid at positions 30 and 31 are Lys Xaa; and the MISC_FEATURE section states Xaa30 is Nle(epsilon-N3), and Xaa31 is gamma-Glu. Therefore, the metes and bounds of instant claims 15, 16 and 26-28 are vague and indefinite.
24. Claims 16 and 28 recite compounds CON117 and CON130. The instant specification discloses CON117 comprises PEP88 and INS32; and CON130 comprises PEP101 and INS32 (see Table 4 in instant specification). However, the instant specification fails to disclose the linking moiety in these compounds. Therefore, it is unclear what the structure of CON117 or CON130 is. Thus, the metes and bounds of instant claims 16 and 28 are vague and indefinite.
Claim Rejections - 35 U.S.C. § 112 paragraph (d)
25. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
26. Claim 6 is rejected under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
27. Claim 6 depends on claim 5; and claim 6 recites "The compound of claim 5, wherein the insulin molecule is a heterodimer molecule or a single-chain insulin molecule". However, the insulin molecule recited in instant claim 5 is either a heterodimer molecule or a single-chain insulin molecule. Therefore, the scope of the compound recited in instant claim 6 is identical to that of the compound recited in instant claim 5. Claim 6 does not further limit the scope of the compound recited in claim 5; and claim 6 is improper dependent form for failing to further limit the subject matter of claim 5.
Please note: in the instant case, the Examiner is interpreting the insulin molecule recited in instant claim 6 broadly includes insulin dimer comprising heterodimer or single-chain insulin.
Claim Rejections - 35 U.S.C. § 103
28. 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 of this title, 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.
29. 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 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
30. Please note: during the search for the elected species, prior art was found for the non-elected species of compound.
Claims 1, 5-9, 17 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Dimarchi et al (WO 2014/158900 A1, filed with IDS) in view of Irwin et al (ChemMedChem, 2015, 10, pages 1424-1434).
The instant claims 1, 5-9, 17 and 29 are drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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; a compound comprising the formula A-LM-B, wherein A is human insulin molecule or human insulin analog molecule; B is a incretin molecule or glucagon peptide modified to have agonist activity at the GLP1 receptor, agonist activity at the GIP receptor, agonist the GLP1 and GCG receptors, or agonist activity at the GLP-1 and GIP receptors; and LM is a linking moiety; and a pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
Dimarchi et al, throughout the patent, teach insulin/incretin conjugate comprising insulin agonist peptide conjugated to incretin, wherein the insulin agonist peptide can be human insulin in either heterodimer form or single-chain form, the incretin includes glucagon related peptide such as glucagon, GLP-1, oxyntomodulin, exendin-4, GIP and derivative thereof; and a pharmaceutical formulation comprising such conjugate and a pharmaceutically acceptable carrier, for example, Abstract; page 18, line 31 to page 19, line 8; page 20, lines 24-29; page 30, lines 1-5; and page 135, lines 2-4. It meets the limitation of insulin molecule recited in instant claims 1, 5-7 and 17; the limitation of the peptide recited in instant claims 1 and 17; and the limitation of a pharmaceutically acceptable carrier recited in instant claim 29. Dimarchi et al further teach the incretin/glucagon related peptide is linked to B1 (N-terminus), B28 or B29 of the B chain of the insulin peptide, for example, page 4, line 30 to page 5, line 10; and page 5, lines 21-23. It meets the limitation of instant claim 8. Dimarchi et al also teach the N-terminus or C-terminus of the insulin peptide is covalently linked to the side chain of an amino acid of the incretin/glucagon related peptide at position 20 or 24, for example page 27, lines 12-15. It meets the limitation of instant claim 9. Furthermore, Dimarchi et al teach the insulin/incretin conjugate can comprise a linker/spacer, for example, page 4, lines 30-32; and page 27, lines 2-4. In addition, Dimarchi et al teach the incretin/glucagon related peptide comprises the amino acid sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 703) or HAEGTFTSDVSSYLEGQAAK
EFICWLVKGR (SEQ ID NO: 717), for example, page 147, lines 1-5.
The difference between the reference and instant claims 1, 5-9, 17 and 29 is that the reference does not explicitly teach the linking moiety recited in instant claims 1 and 17.
However, Irwin et al, throughout the literature, teach PTP with the structure
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as a linker in a bioconjugate comprising GLP-1, wherein the linker forms amide bond with each of the two components in the conjugate, and wherein the conjugation is performed via copper-catalyzed 1,3-dipolar cycloaddition, for example, page 1426, Figure 1; and page 1432, right column, Section “Conjugation of the D-Ala8GLP-1 to the pentasaccharide”.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Dimarchi et al and Irwin et al to develop a compound comprising human insulin in either heterodimer form or single-chain form conjugated to an incretin/glucagon related peptide comprises the amino acid sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 703) or HAEGTFTSDVSSYLEGQAAKEFICWLVKGR (SEQ ID NO: 717) via a linker with the structure
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, wherein one end of the linker forms an amide bond with the amino group of the N-terminal amino acid (B1) of the B-chain of human insulin, and the other end of the linker forms an amide bond with the side chain of K at position 20 of the incretin/glucagon related peptide; and a pharmaceutical formulation comprising such compound and a pharmaceutically acceptable carrier.
One of ordinary skilled in the art would have been motivated to combine the teachings of Dimarchi et al and Irwin et al to develop a compound comprising human insulin in either heterodimer form or single-chain form conjugated to an incretin/glucagon related peptide comprises the amino acid sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 703) or HAEGTFTSDVSSYLEGQAAKEFICWLVKGR (SEQ ID NO: 717) via a linker with the structure
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, wherein one end of the linker forms an amide bond with the amino group of the N-terminal amino acid (B1) of the B-chain of human insulin, and the other end of the linker forms an amide bond with the side chain of K at position 20 of the incretin/glucagon related peptide; and a pharmaceutical formulation comprising such compound and a pharmaceutically acceptable carrier, because Irwin et al, throughout the literature, teach PTP with the structure
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as a linker in a bioconjugate comprising GLP-1, wherein the linker forms amide bond with each of the two components in the conjugate, and wherein the conjugation is performed via copper-catalyzed 1,3-dipolar cycloaddition. The compound developed from the combined teachings of Dimarchi et al and Irwin et al is combining prior art elements according to known methods to yield predictable results (see MPEP § 2143).
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Dimarchi et al and Irwin et al to develop a compound comprising human insulin in either heterodimer form or single-chain form conjugated to an incretin/glucagon related peptide comprises the amino acid sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 703) or HAEGTFTSDVSSYLEGQAAKEFICWLVKGR (SEQ ID NO: 717) via a linker with the structure
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, wherein one end of the linker forms an amide bond with the amino group of the N-terminal amino acid (B1) of the B-chain of human insulin, and the other end of the linker forms an amide bond with the side chain of K at position 20 of the incretin/glucagon related peptide; and a pharmaceutical formulation comprising such compound and a pharmaceutically acceptable carrier.
31. Please note: during the search for the elected species, prior art was found for the non-elected species of compound.
Claims 1, 3, 5-8, 17 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Dimarchi et al (WO 2014/158900 A1, filed with IDS) in view of Avrutina et al (Org. Biomol. Chem., 2009, 7, pages 4177-4185) and Clardy et al (Bioconjugate Chem., 2014, 25, pages 171-177).
The instant claims 1, 3, 5-8, 17 and 29 are drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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; a compound comprising the formula A-LM-B, wherein A is human insulin molecule or human insulin analog molecule; B is a incretin molecule or glucagon peptide modified to have agonist activity at the GLP1 receptor, agonist activity at the GIP receptor, agonist the GLP1 and GCG receptors, or agonist activity at the GLP-1 and GIP receptors; and LM is a linking moiety; and a pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
Dimarchi et al, throughout the patent, teach insulin/incretin conjugate comprising insulin agonist peptide conjugated to incretin, wherein the insulin agonist peptide can be human insulin in either heterodimer form or single-chain form, the incretin includes glucagon related peptide such as glucagon, GLP-1, oxyntomodulin, exendin-4, GIP and derivative thereof; and a pharmaceutical formulation comprising such conjugate and a pharmaceutically acceptable carrier, for example, Abstract; page 18, line 31 to page 19, line 8; page 20, lines 24-29; page 30, lines 1-4; and page 135, lines 2-4. It meets the limitation of insulin molecule recited in instant claims 1, 5-7 and 17; the limitation of peptide recited in instant claims 1 and 17; and the limitation of a pharmaceutically acceptable carrier recited in instant claim 29. Dimarchi et al further teach the incretin/glucagon related peptide is linked to B1 (N-terminus), B28 or B29 of the B chain of the insulin peptide, for example, page 4, line 30 to page 5, line 10; and page 5, lines 21-23. It meets the limitation of instant claim 8. Dimarchi et al also teach the insulin/incretin conjugate can comprise a linker/spacer, for example, page 4, lines 30-32; and page 27, lines 2-4.
The difference between the reference and instant claims 1, 3, 5-8, 17 and 29 is that the reference does not explicitly teach the linking moiety recited in instant claims 1 and 17; and the limitation of instant claim 3.
However, Avrutina et al, throughout the literature, teach peptide conjugate by copper(I) catalyzed azide–alkyne [3+2] cycloaddition via incorporation of propargylglycine (Pra) into one peptide, wherein the propargyl (alkynyl) group of Pra in one peptide reacts with the
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group connected to the N-terminal amino group of the other peptide to form a linker with the structure
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, for example, page 4178, Scheme 1; and pages 4178-4179, Sections “Synthesis of alkyne and azide building blocks” and “Click ligations”.
Furthermore, Clardy et al teach conjugate comprising exendin-4 derivative with Pra at position 12, 27 or C-terminus, wherein the conjugate is prepared via copper(I) catalyzed click chemistry, for example, page 171, right column, Section “Materials”; and page 174, the 1st paragraph in Section “RESULTS”.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Dimarchi et al, Avrutina et al and Clardy et al to develop a compound comprising human insulin in either heterodimer form or single-chain form conjugated to an exendin-4 derivative with Pra at position 12, 27 or C-terminus via a linker with the structure
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, wherein the human insulin comprises
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connected to the N-terminal amino group of the N-terminal amino acid (B1) of the B-chain of human insulin, and wherein the azido group and the propargyl (alkynyl) group in Pra form the 1,4-disubstituted 1,2,3-triazole; and a pharmaceutical formulation comprising such compound and a pharmaceutically acceptable carrier.
One of ordinary skilled in the art would have been motivated to combine the teachings of Dimarchi et al, Avrutina et al and Clardy et al to develop a compound comprising human insulin in either heterodimer form or single-chain form conjugated to an exendin-4 derivative with Pra at position 12, 27 or C-terminus via a linker with the structure
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, wherein the human insulin comprises
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connected to the N-terminal amino group of the N-terminal amino acid (B1) of the B-chain of human insulin, and wherein the azido group and the propargyl (alkynyl) group in Pra form the 1,4-disubstituted 1,2,3-triazole; and a pharmaceutical formulation comprising such compound and a pharmaceutically acceptable carrier, because Avrutina et al, throughout the literature, teach peptide conjugate by copper(I) catalyzed azide–alkyne [3+2] cycloaddition via incorporation of propargylglycine (Pra) into one peptide, wherein the propargyl (alkynyl) group of Pra in one peptide reacts with the
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group connected to the N-terminal amino group of the other peptide to form a linker with the structure
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. Clardy et al teach conjugate comprising exendin-4 derivative with Pra at position 12, 27 or C-terminus, wherein the conjugate is prepared via copper(I) catalyzed click chemistry. The compound developed from the combined teachings of Dimarchi et al, Avrutina et al and Clardy et al is combining prior art elements according to known methods to yield predictable results (see MPEP § 2143).
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Dimarchi et al, Avrutina et al and Clardy et al to develop a compound comprising human insulin in either heterodimer form or single-chain form conjugated to an exendin-4 derivative with Pra at position 12, 27 or C-terminus via a linker with the structure
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, wherein the human insulin molecule comprises
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connected to the N-terminal amino group of the N-terminal amino acid (B1) of the B-chain of human insulin, and wherein the azido group and the propargyl (alkynyl) group in Pra form the 1,4-disubstituted 1,2,3-triazole; and a pharmaceutical formulation comprising such compound and a pharmaceutically acceptable carrier.
32. Claims 15, 16 and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Dimarchi et al (WO 2014/158900 A1, filed with IDS) in view of Palani et al (WO 2017/189342 A1).
The instant claims 15, 16 and 26-28 are drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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, and wherein the peptide is selected from the group consisting of PEP1 to PEP132; a compound comprising a conjugate selected from the group consisting of CON1-CON22, CON24-CON53 and CON55-CON161; a compound comprising an insulin analog selected from the group consisting of INS1-INS31 conjugated to a peptide selected from the group consisting of PEP1-PEP132; and a compound comprising a conjugate selected from the group consisting of CON1-CON22, CON24-CON53, CON55-CON99, and CON101-CON161.
Dimarchi et al, throughout the patent, teach insulin/incretin conjugate comprising insulin agonist peptide conjugated to incretin, wherein the insulin agonist peptide can be human insulin in heterodimer form, the incretin includes glucagon related peptide such as glucagon, GLP-1, oxyntomodulin, exendin-4, GIP and derivative thereof, and wherein all the peptides can comprise a C-terminal amino acid modified with an amide group, for example, Abstract; page 16, lines 13-18; page 18, line 31 to page 19, line 1; page 20, lines 24-29; and page 30, lines 1-4. It meets the limitation of the insulin molecule recited in instant claim 15. Dimarchi et al further teach the incretin/glucagon related peptide is linked to B1 (N-terminus), B28 or B29 of the B chain of the insulin peptide, for example, page 4, line 30 to page 5, line 10. Dimarchi et al also teach the N-terminus or C-terminus of the insulin peptide is covalently linked to the side chain of an amino acid of the incretin/glucagon related peptide at position 20 or 24, for example page 27, lines 12-15. Furthermore, Dimarchi et al teach the insulin/incretin conjugate can comprise a linker/spacer, for example, page 4, lines 30-32; and page 27, lines 2-4.
The difference between the reference and instant claims 15, 16 and 26-28 is that the reference does not explicitly teach the linking moiety and the peptide recited in instant claims 15 and 26; and the limitations of instant claims 16, 27 and 28.
However, Palani et al, throughout the patent, teach insulin/incretin conjugate comprising insulin agonist peptide conjugated to incretin, for example, Abstract. Palani et al further teach the incretin in the conjugate can be PEP69 with azido-norleucine at position 24 (identical to instant PEP69), for example, PEP69 on page 92. Palani et al also teach a linker with the structure
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can be used to connect azido-norleucine in the incretin to the insulin peptide.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Dimarchi et al and Palani et al to develop a compound with the structure
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(identical to instant CON4). It reads on CON4 as the elected species of compound.
One of ordinary skilled in the art would have been motivated to combine the teachings of Dimarchi et al and Palani et al to develop a compound with the structure
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(identical to instant CON4), because Palani et al, throughout the patent, teach insulin/incretin conjugate comprising insulin agonist peptide conjugated to incretin. Palani et al further teach the incretin in the conjugate can be PEP69 with azido-norleucine at position 24 (identical to instant PEP69). Palani et al also teach a linker with the structure
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can be used to connect azido-norleucine in the incretin to the insulin peptide. The compound developed from the combined teachings of Dimarchi et al and Palani et al is combining prior art elements according to known methods to yield predictable results (see MPEP § 2143).
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Dimarchi et al and Palani et al to develop a compound with the structure
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(identical to instant CON4).
Obviousness Double Patenting
33. 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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
34. Claims 1, 3, 5-7, 17 and 29 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-22 of US patent 11058775 B2.
35. Instant claims 1, 3, 5-7, 17 and 29 are drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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; a compound comprising the formula A-LM-B, wherein A is human insulin molecule or human insulin analog molecule; B is a incretin molecule or glucagon peptide modified to have agonist activity at the GLP1 receptor, agonist activity at the GIP receptor, agonist the GLP1 and GCG receptors, or agonist activity at the GLP-1 and GIP receptors; and LM is a linking moiety; and a pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
36. Claims 1-22 of US patent 11058775 B2 are drawn to a compound comprising: an insulin dimer conjugated to a peptide having at least one incretin activity selected from the group consisting of glucagon-like 1 (GLP-1) activity, glucagon (GCG) activity, and gastric inhibitory protein (GIP) activity; a composition comprising such compound and a pharmaceutically acceptable carrier; and a method for treating diabetes comprising administering to an individual with diabetes a therapeutically effective amount of such composition.
In the instant case, in view of the combined teachings of claims 1-22 of US patent 11058775 B2, it would have been obvious to one or ordinary skilled in the art to develop the compound and the pharmaceutic formulations recited in instant claims 1, 3, 5-7, 17 and 29.
37. Claims 1, 3, 5-9, 17 and 29 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-22 of US patent 11058775 B2 in view of Dimarchi et al (WO 2014/158900 A1, filed with IDS).
38. Instant claims 1, 3, 5-9, 17 and 29 are drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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; a compound comprising the formula A-LM-B, wherein A is human insulin molecule or human insulin analog molecule; B is a incretin molecule or glucagon peptide modified to have agonist activity at the GLP1 receptor, agonist activity at the GIP receptor, agonist the GLP1 and GCG receptors, or agonist activity at the GLP-1 and GIP receptors; and LM is a linking moiety; and a pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
39. Claims 1-22 of US patent 11058775 B2 are drawn to a compound comprising: an insulin dimer conjugated to a peptide having at least one incretin activity selected from the group consisting of glucagon-like 1 (GLP-1) activity, glucagon (GCG) activity, and gastric inhibitory protein (GIP) activity; a composition comprising such compound and a pharmaceutically acceptable carrier; and a method for treating diabetes comprising administering to an individual with diabetes a therapeutically effective amount of such composition.
In the instant case, in view of the combined teachings of claims 1-22 of US patent 11058775 B2, it would have been obvious to one or ordinary skilled in the art to develop the compound and the pharmaceutic formulation recited in instant claims 1, 3, 5-7, 17 and 29.
40. The difference between the compound and the pharmaceutic formulation developed from the combined teachings of claims 1-22 of US patent 11058775 B2 above and instant claims 1, 3, 5-9, 17 and 29 is that the compound developed above does not explicitly teach the limitations recited in instant claims 8 and 9.
However, in view of the teachings of Dimarchi et al as set forth in Section 30 above, it would have been obvious to one of ordinary skilled in the art to modify the compound and the pharmaceutic formulation developed from the combined teachings of claims 1-22 of US patent 11058775 B2 and develop the compound and the pharmaceutical formulation recited in instant claims 1, 3, 5-9, 17 and 29.
41. Claims 15 and 26 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-22 of US patent 11058775 B2 in view of Palani et al (WO 2017/189342 A1).
42. Instant claims 15 and 26 are drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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, and wherein the peptide is selected from the group consisting of PEP1 to PEP132.
43. Claims 1-22 of US patent 11058775 B2 are drawn to a compound comprising: an insulin dimer conjugated to a peptide having at least one incretin activity selected from the group consisting of glucagon-like 1 (GLP-1) activity, glucagon (GCG) activity, and gastric inhibitory protein (GIP) activity; a composition comprising such compound and a pharmaceutically acceptable carrier; and a method for treating diabetes comprising administering to an individual with diabetes a therapeutically effective amount of such composition.
In the instant case, in view of the combined teachings of claims 1-22 of US patent 11058775 B2, it would have been obvious to one or ordinary skilled in the art to develop a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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.
44. The difference between the compound developed from the combined teachings of claims 1-22 of US patent 11058775 B2 above and instant claims 15 and 26 is that the compound developed above does not explicitly teach the limitation of the peptide recited in instant claims 15 and 26.
However, in view of the teachings of Palani et al as set forth in Section 32 above, it would have been obvious to one of ordinary skilled in the art to modify the compound developed from the combined teachings of claims 1-22 of US patent 11058775 B2 and develop the compound recited in instant claims 15 and 26.
45. Claims 1, 5-8, 17 and 29 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-18 of US patent 7928058 B2 in view of Dimarchi et al (WO 2014/158900 A1, filed with IDS) and Irwin et al (ChemMedChem, 2015, 10, pages 1424-1434).
46. Instant claims 1, 5-8, 17 and 29 are drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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; a compound comprising the formula A-LM-B, wherein A is human insulin molecule or human insulin analog molecule; B is a incretin molecule or glucagon peptide modified to have agonist activity at the GLP1 receptor, agonist activity at the GIP receptor, agonist the GLP1 and GCG receptors, or agonist activity at the GLP-1 and GIP receptors; and LM is a linking moiety; and a pharmaceutical formulation comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
47. Claims 1-18 of US patent 7928058 B2 are drawn to a polypeptide comprising the amino acid sequence of SEQ ID NO:4, further comprising a substitution of Asp, Glu, Ile, Val, D-Ser, Met, D-Ala, Trp, Asn, Leu, or α-aminoisobutyric acid for the Ser at position 2 and a pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising such polypeptide and a pharmaceutically acceptable carrier; and a method for reducing body weight in a subject in need thereof with such polypeptide.
And as evidenced by the specification of US patent 7928058 B2, the polypeptide recited in claims 1-18 of US patent 7928058 B2 is an oxyntomodulin derivative, which meets the limitation of the peptide recited in instant claims 1 and 17.
48. The difference between claims 1-18 of US patent 7928058 B2 and instant claims 1, 5-8, 17 and 29 is that claims 1-18 of US patent 7928058 B2 do not teach applying the oxyntomodulin derivative in an insulin/incretin conjugate to develop the compound recited in instant claims 1, 5-8, 17 and 29.
However, in view of the combined teachings of Dimarchi et al and Irwin et al as set forth in Section 30 above, it would have been obvious to one of ordinary skilled in the art to apply the oxyntomodulin derivative recited in claims 1-18 of US patent 7928058 B2 in an insulin/incretin conjugate and develop the compound and the pharmaceutical formulation recited in instant claims 1, 5-8, 17 and 29.
49. For the same/similar reasoning/rational as the rejection set forth in Sections 45-48 above, instant claims 1, 5-8, 17 and 29 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-14 of US patent 8268779 B2; claims 1-12 of US patent 8969294 B2; claims 1-10 of US patent 9593155 B2; claims 1-30 of US patent 10413593 B2; claims 1-20 of US patent 10493125B2; claims 1-17 of US patent 10793615 B2; claims 1-7 of US patent 10953076 B2; claims 1-33 of US patent 11492385 B2; and claims 1-24 of US patent 11566057 B2; and in view of the combined teachings of Dimarchi et al (WO 2014/158900 A1, filed with IDS) and Irwin et al (ChemMedChem, 2015, 10, pages 1424-1434) as set forth in Section 30 above.
50. For the same/similar reasoning/rational as the rejection set forth in Sections 45-48 above, instant claims 1, 5-8, 17 and 29 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-17 and 21-24 of co-pending Application No. 17/785279; claims 1-21 and 25-28 of co-pending Application No. 17/785287; and claims 1-24 and 28-31 of co-pending Application No. 17/785772; and in view of the combined teachings of Dimarchi et al (WO 2014/158900 A1, filed with IDS) and Irwin et al (ChemMedChem, 2015, 10, pages 1424-1434) as set forth in Section 30 above.
These are all provisional obviousness-type double patenting rejections because the conflicting claims have not in fact been patented.
51. Claims 1, 5-9, 17 and 29 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-10 of US patent 10017556 B2 in view of Dimarchi et al (WO 2014/158900 A1, filed with IDS) and Irwin et al (ChemMedChem, 2015, 10, pages 1424-1434).
52. Instant claims 1, 5-9, 17 and 29 are drawn to a compound comprising: an insulin molecule having agonist activity at the insulin receptor conjugated via a non-peptide linking moiety to a peptide having agonist activity at the glucagon-like 1 (GLP-1) receptor, the glucagon (GCG) receptor, and/or the gastric inhibitory protein (GIP) receptor, wherein the non-peptide linking moiety comprises the formula
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; a compound com