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. Amendment after Non-final office action filed on 7/20/2026 is acknowledged.
3. Claim filed on 7/20/2026 is acknowledged.
4. Claims 4-6, 9, 10, 13-15 and 30-37 have been cancelled.
5. Claims 1-3, 7, 8, 11, 12 and 16-29 are pending in this application.
6. Claims 26-29 remain withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claims 19-22 remain withdrawn from consideration as being drawn to non-elected species.
7. Applicant elected without traverse Group 1 (claims 1-25) and elected without traverse 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.
Restriction requirement was deemed proper and made FINAL in the previous 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 (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) 1 mM to 20 mM of a phosphate buffer selected from the group consisting of a phosphate buffer and a tris(hydroxymethyl)aminomethane (Tris) buffer; (iii) 5 mg/mL to 150 mg/mL of a tonicity agent selected from the group consisting of mannitol, sucrose, trehalose, propylene glycol, glycerin, sodium chloride and arginine hydrochloride; and (iv) 0.05 - 10.0 mg/mL of an antioxidant selected from the group consisting of EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, histidine, cysteine, methionine, ethanol and N-acetyl cysteine, 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 remain withdrawn from consideration as being drawn to non-elected species. Claims 1-3, 7, 8, 11, 12, 16-18 and 23-25 are examined on the merits in this office action.
Withdrawn Objections
8. Objection to claims 4-18, 23 and 24 is hereby withdrawn in view of Applicant’s amendment to the claim.
Maintained/Revised Objections
9. The drawings remain 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.
10. (Revised due to Applicant’s amendment to the claim) Claim 1 remains objected to for the following minor informality: Claim 1 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 1 as “…and (iv) 0.05 mg/mL to 10.0 mg/mL of an antioxidant…”
11. (Revised due to Applicant’s amendment to the claim) Claims 2, 3 and 25 remain objected to for the following minor informality: 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 of the Non-final office action dated 4/23/2026 for the compound recited in claim 1.
Response to Applicant's Arguments
12. Applicant fails to address all the minor issues in the drawings and these claims, and/or Applicant’s amendments to the claim introduces additional minor issues into instant claim 1. Therefore, these objections are deemed proper and are hereby maintained.
New Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (b)
13 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.
14. Claims 1-3, 7, 11, 12, 16-18, 23 and 24 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.
15. Claim 1 recites “(ii) 1 mM to 20 mM of a phosphate buffer selected from the group consisting of a phosphate buffer and a tris(hydroxymethyl)aminomethane (Tris) buffer”. It is unclear how a Tris buffer can be a phosphate buffer. Therefore, the metes and bounds of instant claim 1 is vague and indefinite. Because claims 2, 3, 7, 11, 12, 16-18, 23 and 24 depend from indefinite claim 1, and none of the dependent claims clarifies the point of confusion, they must also be rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Furthermore, for the purpose of this examination, the Examiner is interpretating the limitation “(ii) 1 mM to 20 mM of a phosphate buffer selected from the group consisting of a phosphate buffer and a tris(hydroxymethyl)aminomethane (Tris) buffer” recited in instant claim 1 as “(ii) 1 mM to 20 mM of a buffer selected from the group consisting of a phosphate buffer and a tris(hydroxymethyl)aminomethane (Tris) buffer”. Such interpretation applies to all the rejections set forth below.
16. Claim 7 recites parenthetical expressions “(Tris)”. The metes and bounds of claim 7 is rendered vague and indefinite by the parenthetical recitation of “(Tris)” because it is unclear as to whether the limitation is part of the instantly claimed subject matter.
Furthermore, for the purpose of this examination, the Examiner is interpretating the buffer recited in instant claim 7 is Tris buffer. Such interpretation applies to all the rejections set forth below.
Maintained/Revised Rejections
Claim Rejections - 35 U.S.C. § 103
17. 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.
18. 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.
19. Please note: During the search for the elected species, prior art was found for the non-elected species of pharmaceutical formulation.
(Revised due to Applicant’s amendment to the claim) Claims 1-3, 7, 8, 16-18, 23 and 24 remain 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 actions).
The instant claims 1-3, 7, 8, 16-18, 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 (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) 1 mM to 20 mM of a phosphate buffer selected from the group consisting of a phosphate buffer and a tris(hydroxymethyl)aminomethane (Tris) buffer; (iii) 5 mg/mL to 150 mg/mL of a tonicity agent selected from the group consisting of mannitol, sucrose, trehalose, propylene glycol, glycerin, sodium chloride and arginine hydrochloride; and (iv) 0.05 - 10.0 mg/mL of an antioxidant selected from the group consisting of EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, histidine, cysteine, methionine, ethanol and N-acetyl cysteine, 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 at a concentration of 10 mg/ml, 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, the buffer and its concentration, the tonicity agent and its concentration, and the pH recited in instant claims 1-3, 7, 8, 23 and 24.
The difference between the reference and instant claims 1-3, 7, 8, 16-18, 23 and 24 is that the reference does not explicitly teach adding antioxidant to such pharmaceutical formulation; and the limitations of instant claims 16-18.
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.
Response to Applicant's Arguments
20. Applicant argues that “the Office has failed to establish a prima facie case of obviousness, and more specifically, because (i) the cited references fail to teach each and every claim element, (ii) the skilled artisan would not have had any reason to combine the teachings of Mezo and Avanti, and (iii) the skilled artisan would not have had a reasonable expectation of success in combing the cited references to arrive at the instantly claimed formulation.”
21. Applicant's arguments have been fully considered but have not been found persuasive.
In the instant case, the Examiner would like to point out that instant claims 1-3, 7, 8, 16-18, 23 and 24 are rejected under 35 U.S.C. 103 (obviousness type), and the rejection is based on the combined teachings of Mezo et al and Avanti with routine optimization; therefore, it is not necessary for each of the cited references to teach all the limitations of instant claims. Furthermore, the Examiner would like to point out that the MPEP states "One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references…" (see MPEP § 2145 IV).
In response to Applicant's arguments about instant rejection:
First, the Examiner understands that Mezo et al do not explicitly teach the pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al comprises an antioxidant; and do not teach the need of adding an antioxidant to such pharmaceutical formulation. However, the Examiner would like to point out that Mezo et al explicitly teach a pharmaceutical formulation comprising such compound and a pharmaceutically acceptable carrier, diluent, or excipient. And the MPEP states “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” (see MPEP § 2111.03 I). Therefore, in the instant case, in view of the teachings of Mezo et al as a whole, one of ordinary skilled in the art would understand and reasonably expect that such pharmaceutical formulation in Mezo et al can further comprise additional excipients such as antioxidant.
Second, the Examiner understands that Avanti does not teach the pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al would need an antioxidant. However, it is well known in the peptide/protein formulation art that oxidation as a primary chemical degradation pathway that can occur in a peptide/protein; and adding antioxidant such as EDTA to a formulation comprising peptide/protein as a strategy for improving peptide/protein stability, as discussed in Avanti, 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., cited and enclosed in the previous office action, see for example, Table 7) and many others. Furthermore, in the instant case, as stated in Section 19 above, Avanti explicilty 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. And the compounds 1-4 in Mezo et al all comprise His, Tyr and Trp. Therefore, considering the state of art regarding peptide/protein formulation and in view of the combined teachings of Mezo et al and Avanti as set forth in Section 19 above, one of ordinary skilled in the art would understand and reasonably expect that oxidation would be an issue with the compounds 1-4 in Mezo et al; and adding antioxidant to the pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al would protect such compound from oxidation.
Third, in the instant case, as stated in Section 19 above, Avanti further explicilty 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. With regards to Applicant’s arguments about the potential adverse effects of chelating agents discussed in Avanti, it appears to the Examiner such concern in Avanti is based on Li et al (Pharmaceutical Research, 1993, 10, pages 1572-1579) and Tsai et al (Pharmaceutical Research, 1993, 10, pages 649-659). However, the Li et al reference is related to the effect of primary structure and external conditions on the oxidation of methionine to methionine sulfoxide by the ascorbate/Fe3+ system (see for example, Abstract). And Tsai et al teach EDTA in formulation comprising acidic fibroblast growth factor (aFGF) prevents metal ion-catalyzed oxidation of cysteine residues (see for example, Abstract; and page 654, Table II). Therefore, in the instant case, one of ordinary skilled in the art would understand and reasonably expect that the teachings of Li et al do not apply to instant rejection; and Tsai et al do not teach EDTA accelerated the oxidation process. Furthermore, it is well known in the art that EDAT as an antioxidant can be used in a pharmaceutic formulation comprising insulinotropic peptide, as discussed in Alessi et al (US 2008/0260840 A1, cited and enclosed in the previous office action) and many others. Therefore, in the instant case, considering the state of art regarding EDTA as an antioxidant in a pharmaceutic formulation comprising peptide/protein, including a pharmaceutic formulation comprising insulinotropic peptide, one of ordinary skilled in the art would understand and reasonably expect the potential adverse effects of chelating agents discussed in Avanti would less likely apply to the pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al.
Fourth, the Examiner understands that the cited prior art references do not teach the concentration of EDTA recited in instant claims. However, in the instant case, as stated in Section 19 above, 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 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 (see MPEP § 2144.05 II A). And in the instant case, other than statements/arguments, Applicant fails to provide any reasoning and/or evidence to indicate the instant claimed concentration of EDTA cannot be achieved via routine optimization. Applicant also fails to provide any data and/or evidenced to indicate the instant claimed concentration of EDTA is critical.
Fifth, with regards to Applicant’s arguments about what is disclosed in instant specification, the Examiner understands that the instant specification discloses compound 1 in Mezo et al tends to undergo fibrillation and oxidation; and such issues can be solved by adding antioxidant to the formulation comprising compound 1 in Mezo et al. However, in the instant case, as stated above, considering the state of art regarding peptide/protein formulation and in view of the combined teachings of Mezo et al and Avanti as set forth in Section 19 above, one of ordinary skilled in the art would understand and reasonably expect that oxidation would be an issue with compounds 1-4 in Mezo et al; and adding antioxidant to the pharmaceutical formulations in Mezo et al would protect compounds 1-4 in these formulations from oxidation. Furthermore, the instant specification discloses that formulating such compound at a pH in the range of 7.8-9.0 to avoid fibrillation. And in the instant case, the pharmaceutical formulation comprising one of compounds 1-4 in Mezo et al has a pH of 8.0. Therefore, one of ordinary skilled in the art would understand and reasonably expect that the pharmaceutical formulation developed from the combined teachings of Mezo et al and Avanti with routine optimization as set forth in Section 19 above would achieve the results disclosed in instant specification. In addition, in the event Applicant is trying to argue about unexpected results, the Examiner would like to bring Applicant’s attention to MPEP § 716.02, which provides the guidelines for allegations of unexpected results.
Sixth, the Examiner would like to point out that the combined teachings of Mezo et al and Avanti with routine optimization as set forth in Section 19 above teach each and every limitation recited in instant claims 1-3, 7, 8, 16-18, 23 and 24. And other than statements/arguments, Applicant fails to point out how and/or why the combination of the cited references does not teach or suggest each and every claim element. Further clarification is required.
Taken all these together, considering the state of art regarding peptide/protein formulation, including the state of art regarding EDTA as an antioxidant in a pharmaceutic formulation comprising peptide/protein, and in view of the combined teachings of Mezo et al and Avanti with routine optimization as set forth in Section 19 above, one of ordinary skilled in the art would have been motivated and/or a person of ordinary skilled in the art would have reasonable expectation of success in developing the pharmaceutical composition recited in instant claims 1-3, 7, 8, 16-18, 23 and 24.
In addition, with regards to the expectation of success, the MPEP states: “Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.” (see MPEP § 2145).
Therefore, the rejection is deemed proper and is hereby maintained.
The Alessi et al, Chang et al, Li et al and Tsai et al references are cited only for the purpose of rebutting Applicant's arguments, therefore, they are not cited as prior art references.
22. (Revised due to Applicant’s amendment to the claim) Claims 1-3, 7, 8, 11, 12, 16-18 and 23-25 remain 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 actions), 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, cited and enclosed in the previous office action) and Alessi et al (US 2008/0260840 A1, cited and enclosed in the previous office action).
The instant claims 1-3, 7, 8, 11, 12, 16-18 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 (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) 1 mM to 20 mM of a phosphate buffer selected from the group consisting of a phosphate buffer and a tris(hydroxymethyl)aminomethane (Tris) buffer; (iii) 5 mg/mL to 150 mg/mL of a tonicity agent selected from the group consisting of mannitol, sucrose, trehalose, propylene glycol, glycerin, sodium chloride and arginine hydrochloride; and (iv) 0.05 - 10.0 mg/mL of an antioxidant selected from the group consisting of EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, histidine, cysteine, methionine, ethanol and N-acetyl cysteine, wherein the pH of the formulation is 7.8 - 9.0.
The rejection to claims 1-3, 7, 8, 16-18, 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 19 above.
The difference between the rejection set forth in Section 19 above and instant claims 1-3, 7, 8, 11, 12, 16-18 and 23-25 is that the rejection set forth in Section 19 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.
Response to Applicant's Arguments
23. Applicant argues that “Applicant reiterates the arguments presented above regarding Mezo and Avanti and respectfully submits that the mere recitation of various excipients in Chang does nothing to remedy the deficiencies of Mezo and Avanti noted above.”
24. Applicant's arguments have been fully considered but have not been found persuasive.
In the instant case, the Examiner would like to point out that instant claims 1-3, 7, 8, 11, 12, 16-18 and 23-25 are rejected under 35 U.S.C. 103 (obviousness type), and the rejection is based on the combined teachings of Mezo et al, Avanti, Chang et al and Alessi et al with routine optimization; therefore, it is not necessary for each of the cited references to teach all the limitations of instant claims. Furthermore, the Examiner would like to point out that the MPEP states "One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references…" (see MPEP § 2145 IV).
Applicant’s arguments on the cited Mezo et al and Avanti references have been addressed in Section 21 above.
With regards to Applicant’s arguments about the cited Chang et al reference, the Examiner understands that Chang et al do not teach the compounds 1-4 in Mezo et al. However, the Examiner would like to point out that Chang et al is a review article that discusses practical approaches to peptide/protein formulation. And the compounds 1-4 in Mezo et al are all peptides. Therefore, it is unclear to the Examiner why and/or how one of ordinary skilled in the art would reach the conclusion that the teachings of Chang et al would not apply to the compounds 1-4 in Mezo et al. Further clarification is required.
With regards to Applicant’s arguments about the cited Alessi et al reference, in the instant case, Alessi et al is cited to teach EDTA as an antioxidant can be added to a pharmaceutical formulation comprising insulinotropic peptide, and the concentrations of EDTA in such formulation. Since the compounds 1-4 in Mezo et al are all insulinotropic peptides, it is unclear to the Examiner why and/or how one of ordinary skilled in the art would reach the conclusion that the teachings of Alessi et al would not apply to the compounds 1-4 in Mezo et al. Further clarification is required.
Taken all these together, the rejection is still deemed proper and is hereby maintained.
Obviousness Double Patenting
25. 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.
26. (Revised due to Applicant’s amendment to the claim) Claims 1-3, 7, 8, 16-18, 23 and 24 remain 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 actions).
27. Instant claims 1-3, 7, 8, 16-18, 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 (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) 1 mM to 20 mM of a phosphate buffer selected from the group consisting of a phosphate buffer and a tris(hydroxymethyl)aminomethane (Tris) buffer; (iii) 5 mg/mL to 150 mg/mL of a tonicity agent selected from the group consisting of mannitol, sucrose, trehalose, propylene glycol, glycerin, sodium chloride and arginine hydrochloride; and (iv) 0.05 - 10.0 mg/mL of an antioxidant selected from the group consisting of EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, histidine, cysteine, methionine, ethanol and N-acetyl cysteine, wherein the pH of the formulation is 7.8 - 9.0.
28. 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.
29. The difference between instant claims 1-3, 7, 8, 16-18, 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 1-3, 7, 8, 16-18, 23 and 24.
However, in view of the combined teachings of Mezo et al and Avanti with routine optimization as set forth in Section 19 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 1-3, 7, 8, 16-18, 23 and 24.
Please note: US 9938335 B2 and instant application share the same Applicant (Eli Lilly and Company).
30. (Revised due to Applicant’s amendment to the claim) For the same and/or similar reasoning/rational as the rejection set forth in Sections 26-29 above, instant claims 1-3, 7, 8, 11, 12, 16-18 and 23-25 remain 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 actions), 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, cited and enclosed in the previous office action) and Alessi et al (US 2008/0260840 A1, cited and enclosed in the previous office action) with routine optimization as set forth in Section 22 above.
Response to Applicant's Arguments
31. Applicant presents the same arguments as set forth in Sections 20 and 23 above.
32. Applicant's arguments have been fully considered but have not been found persuasive.
Applicant’s arguments as set forth in Sections 20 and 23 above have been addressed in Section 21 and 24 above. Therefore, these double patenting rejections are deemed proper. And until a proper terminal disclaimer is filed and approved by the Office, these double patenting rejections are hereby maintained.
Conclusion
Applicant's amendment necessitated the 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.
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658
