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 3/18/2026 is acknowledged.
4. Claim filed on 6/20/2023 is acknowledged.
5. Claims 30-37 have been cancelled.
6. Claims 1-29 are pending in this application.
7. Claims 26-29 are withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claims 19-22 are withdrawn from consideration as being drawn to non-elected species.
8. Claims 1-18 and 23-25 are under examination.
Election/Restrictions
9. Applicant’s election of Group 1 (claims 1-25) and election of a pharmaceutical formulation comprising 1 mg/mL to 100 mg/mL of a compound of the following formula
His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly, wherein Xaa 2 is Aib; Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH2)₁₈COOH; and the C-terminal amino acid is amidated (SEQ ID NO: 1); (ii) 10 mM of Tris buffer; (iii) 46 mg/mL of mannitol; (iii) 0.5 mg/mL of EDTA, wherein the pH of the formulation is 8.0-8.3 as species of pharmaceutical formulation in the reply filed on 3/18/2026 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 pharmaceutical formulation comprising: (i) a compound of the following formula His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Xaa28-Gly-Gly-Pro-Ser-Ser-Gly wherein Xaa2 is Aib; Xaa28 is Glu or Ser; Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with a C14-C24 fatty acid via a linker between the Lys at position 20 and the C14-C24 fatty acid, wherein the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)t, wherein t is 1 or 2; and the C-terminal amino acid is optionally amidated (SEQ ID NO: 5); (ii) a buffer; (iii) a tonicity agent; and (iii) an antioxidant, wherein the pH of the formulation is 7.8 - 9.0. A search was conducted on the elected species; and prior art was found. Claims 19-22 are withdrawn from consideration as being drawn to non-elected species. Claims 1-18 and 23-25 are examined on the merits in this office action.
Specification
10. 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 (see MPEP § 608.01).
Objections
11. The drawings are objected to for the following minor informality:
Figures 1-3 and 6: The background of these figures needs be white.
Figures 4 and 5: The quality of these figures are extremely poor.
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.
12. Claim 1 is objected to for the following minor informality: Applicant is suggested to amend claim 1 as “A pharmaceutical formulation comprising: (i) a compound of the following formula: His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Xaa28-Gly-Gly-Pro-Ser-Ser-Gly (SEQ ID NO: 5), wherein: Xaa2 is Aib; Xaa28 is Glu or Ser; Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with a C14-C24 fatty acid via a linker, wherein the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)t, wherein t is 1 or 2; and wherein the C-terminal amino acid is optionally amidated; (ii) a buffer; (iii) a tonicity agent; and (iv) an antioxidant, wherein the pH of the formulation is 7.8 - 9.0”.
13. Claims 2, 3 and 25 are objected to for the following minor informality: Applicant is required to amend the recited “A pharmaceutical formulation according to claim 1...” as “The pharmaceutical formulation according to claim 1...”.
Furthermore, with regards to the compounds recited in instant claims 2, 3 and 25, Applicant is suggested to make similar changes as suggested in Section 12 above for the compound recited in instant claim 1.
14. Claim 4 is objected to for the following minor informality: Applicant is suggested to amend claim 4 as “The pharmaceutical formulation according to claim 1, wherein the compound is presented at a concentration of from 1 mg/mL to 100 mg/mL”.
15. Claim 5 is objected to for the following minor informality: Applicant is suggested to amend claim 5 as “The pharmaceutical formulation according to claim 1, wherein the buffer is selected from the group consisting of phosphate buffer and tris(hydroxymethyl)aminomethane (Tris) buffer”.
16. Claim 6 is objected to for the following minor informality: Applicant is suggested to amend claim 6 as “The pharmaceutical formulation according to claim 1, wherein the buffer is presented at a concentration of from 1 mM to 20 mM”.
17. Claim 7 is objected to for the following minor informality: Applicant is suggested to amend claim 7 as “The pharmaceutical formulation according to claim 5, wherein the buffer is Tris buffer”.
18. Claim 8 is objected to for the following minor informality: Applicant is suggested to amend claim 8 as “The pharmaceutical formulation according to claim 7, wherein the Tris buffer is presented at a concentration of 10 mM”.
19. Claims 9, 11, 16, 23 and 24 are objected to for the following minor informality: Applicant is suggested to amend these claims as “The pharmaceutical formulation according to claim…”.
20. Claim 10 is objected to for the following minor informality: Applicant is suggested to amend claim 10 as “The pharmaceutical formulation according to claim 1, wherein the tonicity agent is presented at a concentration of from 5 mg/mL to 150 mg/mL”.
21. Claim 12 is objected to for the following minor informality: Applicant is suggested to amend claim 12 as “The pharmaceutical formulation according to claim 11, wherein the mannitol is presented at a concentration of from 45 mg/mL to 55 mg/mL”.
22. Claim 13 is objected to for the following minor informality: Applicant is suggested to amend claim 13 as “The pharmaceutical formulation according to claim 1, wherein the antioxidant is selected from the group consisting of radical scavengers, chelators and chain terminators”.
23. Claim 14 is objected to for the following minor informality: Applicant is suggested to amend claim 14 as “The pharmaceutical formulation according to claim 1, wherein the antioxidant is presented at a concentration of from 0.05 mg/mL to 10.0 mg/mL”.
24. Claim 15 is objected to for the following minor informality: Claim 15 contains the acronym “EDTA”. An acronym in the first instance of claims should be expanded upon/spelled out with the acronym indicated in parentheses, i.e., ethylenediaminetetraacetic acid (EDTA). The abbreviation can be used thereafter.
Furthermore, Applicant is suggested to amend claim 15 as “The pharmaceutical formulation according to claim 1, wherein the antioxidant is…”.
25. Claim 17 is objected to for the following minor informality: Applicant is suggested to amend claim 17 as “The pharmaceutical formulation according to claim 16, wherein the EDTA is presented at a concentration of from 0.2 mg/mL to 1.0 mg/mL”.
26. Claim 18 is objected to for the following minor informality: Applicant is suggested to amend claim 18 as “The pharmaceutical formulation according to claim 17, wherein the EDTA is presented at a concentration of 0.5 mg/mL”.
Rejections
Claim Rejections - 35 U.S.C. § 103
27. 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.
28. 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.
29. Please note: During the search for the elected species, prior art was found for the non-elected species of pharmaceutical formulation.
Claims 1-10, 13-18, 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al (US 9938335 B2, filed with IDS) in view of Avanti (Innovative strategies for stabilization of therapeutic peptides in aqueous formulations, 2012, pages 1-157, cited and enclosed in the previous office action).
The instant claims 1-10, 13-18, 23 and 24 are drawn to a pharmaceutical formulation comprising: (i) a compound of the following formula His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Xaa28-Gly-Gly-Pro-Ser-Ser-Gly wherein Xaa2 is Aib; Xaa28 is Glu or Ser; Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with a C14-C24 fatty acid via a linker between the Lys at position 20 and the C14-C24 fatty acid, wherein the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)t, wherein t is 1 or 2; and the C-terminal amino acid is optionally amidated (SEQ ID NO: 5); (ii) a buffer; (iii) a tonicity agent; and (iii) an antioxidant, wherein the pH of the formulation is 7.8 - 9.0.
Mezo et al, throughout the patent, teach a pharmaceutical formulation comprising glucagon and GLP-1 coagonist compound, for example, Abstract; and claims 12 and 13. Mezo et al further teach a pharmaceutical formulation comprising one of compounds 1-4 (SEQ ID NOs: 5-8, respectively) at a concentration of 10 mg/ml, 10 mM Tris, and 150 mM NaCl; wherein the pH of the pharmaceutical formulation is 8.0, for example, columns 18-22, compounds 1-4; and column 24, lines 18-21 and Table 2(a). Compound 1 (SEQ ID NO: 5) in Mezo et al is identical to the compound of instant SEQ ID NO: 3, Compound 2 (SEQ ID NO: 6) in Mezo et al is identical to the compound of instant SEQ ID NO: 1, Compound 3 (SEQ ID NO: 7) in Mezo et al is identical to the compound of instant SEQ ID NO: 4, and Compound 4 (SEQ ID NO: 8) in Mezo et al is identical to the compound of instant SEQ ID NO: 2. And NaCl (molecular weight 58.44) at a concentration of 150 mM equals to NaCl at a concentration of 8.76 mg/ml. Therefore, the pharmaceutical formulation comprising one of compounds 1-4, 10 mM Tris, and 150mM NaCl; wherein the pH of the pharmaceutical formulation is 8.0 in Mezo et al meets the limitations of the compound and its concentration, the buffer and its concentration, the tonicity agent and its concentration, and the pH recited in instant claims 1-10, 23 and 24.
The difference between the reference and instant claims 1-10, 13-18, 23 and 24 is that the reference does not explicitly teach adding antioxidant to such pharmaceutical formulation; and the limitations of instant claims 13-18.
However, Avanti teaches oxidation as a primary chemical degradation pathway that can occur in a peptide; and any peptide that contains cysteine (Cys), methionine (Met), histidine (His), tyrosine (Tyr) and tryptophan (Trp) residues can potentially be damaged due to their high reactivity with various reactive oxygen species (ROS); Cys and Met are at risk for oxidation because of their sulfur atoms, and His, Tyr and Trp because of their aromatic rings, for example, page 21, Section “2.2 Oxidation pathways”. Avanti further teaches chelating agents are used to reduce free radical oxidation and inhibit oxidation by complexation of trace metal ions, wherein the chelating agent can be EDTA and many others, for example, page 27, Section “3.2.4 Chelating agents”.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Mezo et al and Avanti to develop a pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al (identical to the compounds of instant SEQ ID NOs: 1-4) at a concentration of 10 mg/ml, 10 mM Tris, 150mM NaCl (equals to 8.76 mg/ml NaCl), and EDTA as antioxidant/chelating agent; wherein the pH of the pharmaceutical formulation is 8.0.
Furthermore, one of ordinary skilled in the art would have been motivated to optimize the concentration of EDTA in the pharmaceutical formulation developed from the combined teachings of Mezo et al and Avanti above for better stability of the compound in the formulation, including EDTA at a concentration of 0.2-1.0 mg/ml, such as 0.5 mg/ml. And, the MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (see MPEP § 2144.05 II A).
One of ordinary skilled in the art would have been motivated to combine the teachings of Mezo et al and Avanti with routine optimization to develop a pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al (identical to the compounds of instant SEQ ID NOs: 1-4) at a concentration of 10 mg/ml, 10 mM Tris, 150mM NaCl (equals to 8.76 mg/ml NaCl), and EDTA as antioxidant/chelating agent at a concentration of 0.2-1.0 mg/ml, such as 0.5 mg/ml; wherein the pH of the pharmaceutical formulation is 8.0, because Avanti teaches oxidation as a primary chemical degradation pathway that can occur in a peptide; and any peptide that contains cysteine (Cys), methionine (Met), histidine (His), tyrosine (Tyr) and tryptophan (Trp) residues can potentially be damaged due to their high reactivity with various reactive oxygen species (ROS). Avanti further teaches chelating agents are used to reduce free radical oxidation and inhibit oxidation by complexation of trace metal ions, wherein the chelating agent can be EDTA and many others.
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Mezo et al and Avanti with routine optimization to develop a pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al (identical to the compounds of instant SEQ ID NOs: 1-4) at a concentration of 10 mg/ml, 10 mM Tris, 150mM NaCl (equals to 8.76 mg/ml NaCl), and EDTA as antioxidant/chelating agent at a concentration of 0.2-1.0 mg/ml, such as 0.5 mg/ml; wherein the pH of the pharmaceutical formulation is 8.0.
30. Claims 1-18 and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al (US 9938335 B2, filed with IDS) in view of Avanti (Innovative strategies for stabilization of therapeutic peptides in aqueous formulations, 2012, pages 1-157, cited and enclosed in the previous office action), and further in view of Chang et al (PRACTICAL APPROACHES TO PROTEIN FORMULATION DEVELOPMENT, in "Rationale Design of stable protein formulations-theory and practice" (JF. Carpenter and M.C. Manning eds.) Kluwer Academic/Plenum publishers, New York, 2002, pages 1-20) and Alessi et al (US 2008/0260840 A1).
The instant claims 1-18 and 23-25 are drawn to a pharmaceutical formulation comprising: (i) a compound of the following formula His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Xaa28-Gly-Gly-Pro-Ser-Ser-Gly wherein Xaa2 is Aib; Xaa28 is Glu or Ser; Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with a C14-C24 fatty acid via a linker between the Lys at position 20 and the C14-C24 fatty acid, wherein the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)t, wherein t is 1 or 2; and the C-terminal amino acid is optionally amidated (SEQ ID NO: 5); (ii) a buffer; (iii) a tonicity agent; and (iii) an antioxidant, wherein the pH of the formulation is 7.8 - 9.0.
The rejection to claims 1-10, 13-18, 23 and 24 under 35 U.S.C. 103 as being unpatentable over Mezo et al (US 9938335 B2, filed with IDS) in view of Avanti (Innovative strategies for stabilization of therapeutic peptides in aqueous formulations, 2012, pages 1-157, cited and enclosed in the previous office action) has been set forth in Section 29 above.
The difference between the rejection set forth in Section 29 above and instant claims 1-18 and 23-25 is that the rejection set forth in Section 29 above does not explicilty teach a pharmaceutical formulation comprising 1 mg/mL to 100 mg/mL of a compound of the following formula His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly, wherein Xaa 2 is Aib; Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH2)₁₈COOH; and the C-terminal amino acid is amidated (SEQ ID NO: 1); (ii) 10 mM of Tris buffer; (iii) 46 mg/mL of mannitol; (iii) 0.5 mg/mL of EDTA, wherein the pH of the formulation is 8.0-8.3 as the elected species of pharmaceutical formulation; and the limitations of instant claims 11, 12 and 25.
However, Chang et al teach various important components of protein/peptide formulation, including pH, stabilizer such as antioxidants, solubilizer, buffer and tonicity modifier; and similar to sodium chloride in the pharmaceutical formulation in Mezo et al, mannitol is a tonicity modifier, for example, page 12, Table 7. Therefore, in view of the combined teachings of Mezo et al, Avanti and Chang et al with routine optimization, it would have been obvious to one of ordinary skilled in the art to develop a pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al (identical to the compounds of instant SEQ ID NOs: 1-4) at a concentration of 10 mg/ml, 10 mM Tris, either mannitol or 150mM NaCl (equals to 8.76 mg/ml NaCl) as tonicity agent, and EDTA as antioxidant/chelating agent at a concentration of 0.2-1.0 mg/ml, such as 0.5 mg/ml; wherein the pH of the pharmaceutical formulation is 8.0.
Furthermore, Alessi et al, throughout the patent, teach a pharmaceutical formulation comprising insulinotropic peptide, for example, Abstract. Alessi et al further teach such pharmaceutical formulation further comprises carbohydrate such as mannitol as a stabilizer, and antioxidant such as EDTA, for example, page 1, paragraphs [0007], [0012] and [0013]; page 4, paragraph [0053]; and page 6, paragraphs [0081], [0082] and [0086]. Alessi et al also teach the concentration of carbohydrate and/or antioxidant in the formulation can be 0.1 to 30% (by weight); and various concentration ratios between the peptide and the antioxidant in the formulation, for example, page 7, paragraphs [0090] and [0091]. Therefore, in view of the teachings of Alessi et al as a whole, one of ordinary skilled in the art would have been motivated to optimize the concentrations of mannitol and EDTA in the pharmaceutical formulation developed from the combined teachings of Mezo et al, Avanti and Chang et al above for better stability of the compound in the formulation, including a pharmaceutical formulation comprising 1 mg/mL to 100 mg/mL of a compound of instant SEQ ID NO: 1, 10 mM of Tris buffer, 46 mg/mL of mannitol and 0.5 mg/mL of EDTA, wherein the pH of the formulation is 8.0. It reads on a pharmaceutical formulation comprising 1 mg/mL to 100 mg/mL of a compound of the following formula His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly, wherein Xaa 2 is Aib; Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with ([2-(2-aminoethoxy)-ethoxy]-acetyl)₂-(γ-Glu)-CO-(CH2)₁₈COOH; and the C-terminal amino acid is amidated (SEQ ID NO: 1); (ii) 10 mM of Tris buffer; (iii) 46 mg/mL of mannitol; (iii) 0.5 mg/mL of EDTA, wherein the pH of the formulation is 8.0-8.3 as the elected species of pharmaceutical formulation. And, the MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (see MPEP § 2144.05 II A).
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings Mezo et al, Avanti, Chang et al and Alessi et al with routine optimization to develop a pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al (identical to the compounds of instant SEQ ID NOs: 1-4) at a concentration of 10 mg/ml, 10 mM Tris, either 45-55 mg/ml mannitol or 150mM NaCl (equals to 8.76 mg/ml NaCl) as tonicity agent, and 0.2-1.0 mg/ml EDTA as antioxidant/chelating agent; wherein the pH of the pharmaceutical formulation is 8.0, including a pharmaceutical formulation comprising 1 mg/mL to 100 mg/mL of a compound of instant SEQ ID NO: 1, 10 mM of Tris buffer, 46 mg/mL of mannitol and 0.5 mg/mL of EDTA, wherein the pH of the formulation is 8.0.
One of ordinary skilled in the art would have been motivated to combine the teachings of Mezo et al, Avanti, Chang et al and Alessi et al with routine optimization to develop a pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al (identical to the compounds of instant SEQ ID NOs: 1-4) at a concentration of 10 mg/ml, 10 mM Tris, either 45-55 mg/ml mannitol or 150mM NaCl (equals to 8.76 mg/ml NaCl) as tonicity agent, and 0.2-1.0 mg/ml EDTA as antioxidant/chelating agent; wherein the pH of the pharmaceutical formulation is 8.0, including a pharmaceutical formulation comprising 1 mg/mL to 100 mg/mL of a compound of instant SEQ ID NO: 1, 10 mM of Tris buffer, 46 mg/mL of mannitol and 0.5 mg/mL of EDTA, wherein the pH of the formulation is 8.0, because Chang et al teach various important components of protein/peptide formulations, such as pH, stabilizer such as antioxidants, solubilizer, buffer and tonicity modifier; and similar to sodium chloride in the pharmaceutical formulation in Mezo et al, mannitol is a tonicity modifier. Therefore, in view of the combined teachings of Mezo et al, Avanti and Chang et al with routine optimization, it would have been obvious to one of ordinary skilled in the art to develop a pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al (identical to the compounds of instant SEQ ID NOs: 1-4) at a concentration of 10 mg/ml, 10 mM Tris, either mannitol or 150mM NaCl (equals to 8.76 mg/ml NaCl) as tonicity agent, and EDTA as antioxidant/chelating agent at a concentration of 0.2-1.0 mg/ml, such as 0.5 mg/ml; wherein the pH of the pharmaceutical formulation is 8.0. Alessi et al, throughout the patent, teach a pharmaceutical formulation comprising insulinotropic peptide. Alessi et al further teach such pharmaceutical formulation further comprises carbohydrate such as mannitol as a stabilizer, and antioxidant such as EDTA. Alessi et al also teach the concentration of carbohydrate and/or antioxidant in the formulation can be 0.1 to 30% (by weight); and various concentration ratios between the peptide and antioxidant in the formulation. Therefore, in view of the teachings of Alessi et al as a whole, one of ordinary skilled in the art would have been motivated to optimize the concentrations of mannitol and EDTA in the pharmaceutical formulation developed from the combined teachings of Mezo et al, Avanti and Chang et al for better stability of the compound in the formulation. And, the MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical (see MPEP § 2144.05 II A).
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Mezo et al, Avanti, Chang et al and Alessi et al with routine optimization to develop a pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al (identical to the compounds of instant SEQ ID NOs: 1-4) at a concentration of 10 mg/ml, 10 mM Tris, either 45-55 mg/ml mannitol or 150mM NaCl (equals to 8.76 mg/ml NaCl) as tonicity agent, and 0.2-1.0 mg/ml EDTA as antioxidant/chelating agent; wherein the pH of the pharmaceutical formulation is 8.0, including a pharmaceutical formulation comprising 1 mg/mL to 100 mg/mL of a compound of instant SEQ ID NO: 1, 10 mM of Tris buffer, 46 mg/mL of mannitol and 0.5 mg/mL of EDTA, wherein the pH of the formulation is 8.0.
Obviousness Double Patenting
31. 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.
32. Claims 1-10, 13-18, 23 and 24 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 12-18 of US patent 9938335 B2 and in view of Mezo et al (US 9938335 B2, filed with IDS) and Avanti (Innovative strategies for stabilization of therapeutic peptides in aqueous formulations, 2012, pages 1-157, cited and enclosed in the previous office action).
33. Instant claims 1-10, 13-18, 23 and 24 are drawn to a pharmaceutical formulation comprising: (i) a compound of the following formula His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Xaa28-Gly-Gly-Pro-Ser-Ser-Gly wherein Xaa2 is Aib; Xaa28 is Glu or Ser; Lys at position 20 is chemically modified by conjugation of the epsilon-amino group of the Lys side chain with a C14-C24 fatty acid via a linker between the Lys at position 20 and the C14-C24 fatty acid, wherein the linker is ([2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)t, wherein t is 1 or 2; and the C-terminal amino acid is optionally amidated (SEQ ID NO: 5); (ii) a buffer; (iii) a tonicity agent; and (iii) an antioxidant, wherein the pH of the formulation is 7.8 - 9.0.
34. Claims 12-18 of US patent 9938335 B2 are drawn to a compound of SEQ ID NO: 6 or a pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof; and various methods of using such pharmaceutical composition.
The compound of SEQ ID NO: 6 recited in claims 12-18 of US patent 9938335 B2 is identical to the compound of instant SEQ ID NO: 1.
35. The difference between instant claims 1-10, 13-18, 23 and 24 and claims 12-18 of US patent 9938335 B2 is that claims 12-18 of US patent 9938335 B2 do not teach apply the compound recited in claims 12-18 of US patent 9938335 B2 in a pharmaceutical formulation recited in instant claims 1-10, 13-18, 23 and 24.
However, in view of the combined teachings of Mezo et al and Avanti with routine optimization as set forth in Section 29 above, it would have been obvious to one of ordinary skilled in the art to apply the compound recited in claims 12-18 of US patent 9938335 B2 in a pharmaceutical formulation recited in instant claims 1-10, 13-18, 23 and 24.
Please note: US 9938335 B2 and instant application share the same Applicant (Eli Lilly and Company).
36. For the same and/or similar reasoning/rational as the rejection set forth in Sections 32-35 above, instant claims 1-18 and 23-25 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 12-18 of US patent 9938335 B2 and in view of the combined teachings of Mezo et al (US 9938335 B2, filed with IDS), Avanti (Innovative strategies for stabilization of therapeutic peptides in aqueous formulations, 2012, pages 1-157, cited and enclosed in the previous office action), Chang et al (PRACTICAL APPROACHES TO PROTEIN FORMULATION DEVELOPMENT, in "Rationale Design of stable protein formulations-theory and practice" (JF. Carpenter and M.C. Manning eds.) Kluwer Academic/Plenum publishers, New York, 2002, pages 1-20) and Alessi et al (US 2008/0260840 A1) with routine optimization as set forth in Section 30 above.
Conclusion
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658
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