A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/30/2025 has been entered.
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. Response to Final office action filed on 7/30/2025 is acknowledged.
3. Claims 4 and 6-8 have been cancelled.
4. Claims 1-3, 5 and 9-20 are pending in this application.
5. Claims 9-20 remain withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Claim 2 remains withdrawn from consideration as being drawn to non-elected species.
6. Applicant elected without traverse of Group 1 (claims 1-8) and elected GLP-1(7-36) with the amino acid sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR as species of insulinotropic peptide; mannitol as species of isotonic agent; propylene glycol as species of dissolution enhancer; phenol as species of preservative; and NaAc-HAc as species of buffer salt solution in the reply filed on 11/14/2016.
Restriction requirement was deemed proper and made FINAL in the previous office actions. Group 1 is drawn to a multi-dose injectable aqueous parenteral pharmaceutical composition comprising glucagon-like peptide 1 (GLP-1), mannitol, propylene glycol, phenol, and a pharmaceutically acceptable buffer salt solution of sodium acetate-acetic acid (NaAc-HAc), wherein: the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2; the GLP-1 is present at a concentration of 0.1 mg/mL to 20 mg/mL; phenol is present at a concentration of about 1.5 mg/mL to 3 mg/mL; and the GLP-1 is GLP-1(7-36). A search was conducted on the elected species; and prior art was found. Claim 2 remains withdrawn from consideration as being drawn to non-elected species. Claims 1, 3 and 5 are examined on the merits in this office action.
Maintained Rejection
Claim Rejections - 35 U.S.C. § 103
7. 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.
8. 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.
9. Claims 1, 3 and 5 remain rejected under 35 U.S.C. 103 as being unpatentable over Holmquist et al (US 2002/0061838 A1, cited and enclosed in the previous office actions) in view of Izutsu (Therapeutic proteins, methods and protocols, Humana press, edited by C. Mark Smales and David C. James, 2005, pages 287-292, cited and enclosed in the previous office actions), Rinella Jr. (US 6440930 B1, filed with IDS), Toda et al (US 2009/0105130 A1, cited and enclosed in the previous office actions) and Föger (US 2011/0293714 A1, cited and enclosed in the previous office actions).
The instant claims 1, 3 and 5 are drawn to a multi-dose injectable aqueous parenteral pharmaceutical composition comprising glucagon-like peptide 1 (GLP-1), mannitol, propylene glycol, phenol, and a pharmaceutically acceptable buffer salt solution of sodium acetate-acetic acid (NaAc-HAc), wherein: the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2; the GLP-1 is present at a concentration of 0.1 mg/mL to 20 mg/mL; phenol is present at a concentration of about 1.5 mg/mL to 3 mg/mL; and the GLP-1 is GLP-1(7-36).
Holmquist et al, throughout the patent, teach an injectable aqueous parenteral pharmaceutical composition comprising GLP-1 or analog thereof, D-mannitol as isotonic agent and sodium acetate-acetic acid (NaAc-HAc) as a pharmaceutically acceptable buffer salt solution; wherein the aqueous parenteral pharmaceutical composition has a pH of 3.0 to 5.0, and wherein the GLP-1 analog can be GLP-1(7-36) with the amino acid sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR, for example, Abstract; page 1, paragraph [0002]; page 2, paragraphs [0013], [0019] and [0022]; page 3, paragraphs [0031], [0035], [0040] and [0041]; page 4, paragraph [0044]; page 6, paragraphs [0058]-[0061]; and page 8, Example 1. It reads on GLP-1(7-36) with the amino acid sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR as the elected species of insulinotropic peptide; mannitol as the elected species of isotonic agent; and NaAc-HAc as the elected species of buffer salt solution. It meets the limitations of GLP-1(7-36), mannitol, and NaAc-HAc recited in instant claim 1. Holmquist et al further teach the concentration of GLP-1 or analog thereof in the formulation is preferably in the range of about 25 μg to 5 mg per 1 mL of the combination of buffer and diluent; the buffer preferably has a molarity of between about 1 mM and 20 mM, more preferably in the range of between about 5 and 10 mM; and a GLP-1 formulation comprising 1 mg/mL GLP-1 dissolved in 10 mM sodium acetate, 5.07% D-mannitol (equal to 50.7 mg/mL), for example, page 3, paragraphs [0031], [0035] and [0041]; page 6, paragraph [0059]; and page 8, Example 1. It meets the limitation of concentration of GLP-1(7-36) recited in instant claim 1; and the limitations of instant claims 3 and 5. Holmquist et al also teach the GLP-1 or analog thereof formulation can further comprise a pharmaceutically acceptable preservative, a detergent/dissolution enhancer such as Tween 80, or a solvent to increase the solubility of the peptide, for example, page 8, paragraph [0083].
The difference between the reference and instant claims 1, 3 and 5 is that the reference does not teach phenol as the elected species of preservative and propylene glycol as the elected species of dissolution enhancer; and the limitation of “multi-dose” recited in instant claim 1.
However, Izutsu, throughout the literature, teaches that for peptide/protein formulation, preservative such as phenol can be added at a concentration of 1-10 mg/ml for antimicrobial preservation, for example, page 288, Table 2. It reads on phenol as the elected species of preservative. Izutsu further teaches that for peptide/protein formulation, surfactant such as Tween-40 and Tween-80 at a concentration of less than 1 mg/ml can be added as solubilizer, stabilizer and aggregation inhibitor, for example, page 288, Table 2.
Furthermore, Rinella Jr., throughout the patent, teaches a multi-dose injectable aqueous formulation comprising a medically useful peptide or protein, a hydrophobic preservative, and nicotinamide, for example, Abstract; and column 2, lines 1-5 and 33-42. Rinella Jr. further teaches the medically useful peptide or protein can be GLP-1 or analog or derivative thereof such as GLP-1(7-36); the more highly preferred preservative is phenol, the total concertation of preservative is preferably between about 1 mg/mL and 10 mg/mL; and the concentration of preservative is that required to maintain preservative effectiveness, which, in turn, may depend on the preservative, its solubility, and the temperature and the pH of the formulation, for example, column 3, line 17; column 4, line 3; column 5, line 50; column 6, line 9 to column 8, line 21; and claims 1-18. It reads on phenol as the elected species of preservative. Therefore, in view of the combined teachings of Holmquist et al, Izutsu and Rinella Jr., it would have been obvious to one of ordinary skilled in the art to develop a multi-dose injectable aqueous parenteral pharmaceutical composition comprising GLP-1(7-36), mannitol as a pharmaceutically acceptable osmotic agent at a concentration such as 50.7 mg/mL, phenol as a pharmaceutically acceptable preservative at a concentration of 1-10 mg/mL, Tween 40 or Tween 80 as a pharmaceutically acceptable dissolution enhancer, and NaAc-HAc as a pharmaceutically acceptable buffer salt solution; wherein the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2, and GLP-1(7-36) is present at a concentration of 0.1 mg/mL to 20 mg/mL such as 1 mg/mL.
And in the instant case, the instant claimed concentration of phenol as a pharmaceutically acceptable preservative (about 1.5 mg/mL to 3 mg/mL) overlaps and/or lies inside ranges disclosed by the prior art (1-10 mg/mL taught in both Izutsu and Rinella Jr.), the MPEP states that “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…” (see MPEP § 2144.05 I).
In addition, Todd et al teach propylene glycol as a dissolution enhancer for peptide/protein formulation, for example, page 1, paragraph [0014]; page 2, paragraphs [0022], [0043] and [0044]; and page 3, paragraph [0053]. It reads on propylene glycol as the elected species of dissolution enhancer.
And, Föger teaches that propylene glycol as a dissolution enhancer is biocompatible even at high dosages and has a high solvent capacity for GLP-1 compounds, for example, page 7, paragraph [0082]. It reads on propylene glycol as the elected species of dissolution enhancer.
Furthermore, one of ordinary skilled in the art would have been motivated to optimize the pH of the composition, and the concentrations of GLP-1(7-36), mannitol and phenol in the composition, since it is the normal desire of scientists or artisans to improve upon what is already generally known. And Rinella Jr. explicitly teaches in multi-dose injectable aqueous formulation comprising GLP-1 or analog or derivative thereof such as GLP-1(7-36); the more highly preferred preservative is phenol, the total concertation of preservative is preferably between about 1 mg/mL and 10 mg/mL; and the concentration of preservative is that required to maintain preservative effectiveness, which, in turn, may depend on the preservative, its solubility, and the temperature and the pH of the formulation. 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 substitute and/or try Tween 40 or Tween 80 as a pharmaceutically acceptable dissolution enhancer taught in Izutsu with propylene glycol taught in both Todd et al and Föger, and in view of the combined teachings of Holmquist et al, Izutsu, Rinella Jr., Todd et al and Föger with routine optimization to develop a multi-dose injectable aqueous parenteral pharmaceutical composition comprising GLP-1(7-36), mannitol as a pharmaceutically acceptable osmotic agent at a concentration such as 50.7 mg/mL, phenol as a pharmaceutically acceptable preservative at a concentration of about 1.5 mg/mL to 3 mg/mL, propylene glycol as a pharmaceutically acceptable dissolution enhancer, and NaAc-HAc as a pharmaceutically acceptable buffer salt solution; wherein the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2, and the GLP-1(7-36) is present at a concentration of 0.1 mg/mL to 20 mg/mL such as 1 mg/mL.
One of ordinary skilled in the art would have been motivated to substitute and/or try Tween 40 or Tween 80 as a pharmaceutically acceptable dissolution enhancer taught in Izutsu with propylene glycol taught in both Todd et al and Föger, and in view of the combined teachings of Holmquist et al, Izutsu, Rinella Jr., Todd et al and Föger with routine optimization to develop a multi-dose injectable aqueous parenteral pharmaceutical composition comprising GLP-1(7-36), mannitol as a pharmaceutically acceptable osmotic agent at a concentration such as 50.7 mg/mL, phenol as a pharmaceutically acceptable preservative at a concentration of about 1.5 mg/mL to 3 mg/mL, propylene glycol as a pharmaceutically acceptable dissolution enhancer, and NaAc-HAc as a pharmaceutically acceptable buffer salt solution; wherein the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2, and the GLP-1(7-36) is present at a concentration of 0.1 mg/mL to 20 mg/mL such as 1 mg/mL, because Izutsu teaches that for peptide/protein formulation, preservative such as phenol can be added at a concentration of 1-10 mg/ml for antimicrobial preservation. Izutsu further teaches that for peptide/protein formulation, surfactant such as Tween-40 and Tween-80 at a concentration of less than 1 mg/ml can be added as solubilizer, stabilizer and aggregation inhibitor. Rinella Jr. teaches a multi-dose injectable aqueous formulation comprising a medically useful peptide or protein, a hydrophobic preservative, and nicotinamide. Rinella Jr. further teaches the medically useful peptide or protein can be GLP-1 or analog or derivative thereof such as GLP-1(7-36); the more highly preferred preservative is phenol, and the total concertation of preservative is preferably between about 1 mg/mL and 10 mg/mL. Todd et al teach propylene glycol as a dissolution enhancer for peptide/protein formulation. Föger teaches that propylene glycol as a dissolution enhancer is biocompatible even at high dosages and has a high solvent capacity for GLP-1 compounds. Furthermore, one of ordinary skilled in the art would have been motivated to optimize the pH of the composition, and the concentrations of GLP-1(7-36), mannitol and phenol in the composition, since it is the normal desire of scientists or artisans to improve upon what is already generally known. And Rinella Jr. explicitly teaches in multi-dose injectable aqueous formulation comprising GLP-1 or analog or derivative thereof such as GLP-1(7-36), the more highly preferred preservative is phenol, the total concertation of preservative is preferably between about 1 mg/mL and 10 mg/mL; and the concentration of preservative is that required to maintain preservative effectiveness, which, in turn, may depend on the preservative, its solubility, and the temperature and the pH of 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 substituting and/or trying Tween 40 or Tween 80 as a pharmaceutically acceptable dissolution enhancer taught in Izutsu with propylene glycol taught in both Todd et al and Föger, and in view of the combined teachings of Holmquist et al, Izutsu, Rinella Jr., Todd et al and Föger with routine optimization to develop a multi-dose injectable aqueous parenteral pharmaceutical composition comprising GLP-1(7-36), mannitol as a pharmaceutically acceptable osmotic agent at a concentration such as 50.7 mg/mL, phenol as a pharmaceutically acceptable preservative at a concentration of about 1.5 mg/mL to 3 mg/mL, propylene glycol as a pharmaceutically acceptable dissolution enhancer, and NaAc-HAc as a pharmaceutically acceptable buffer salt solution; wherein the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2, and the GLP-1(7-36) is present at a concentration of 0.1 mg/mL to 20 mg/mL such as 1 mg/mL.
Response to Applicant's Arguments
10. Applicant argues that the Office Action fails to establish reasonable expectation of success of the stability of instant claimed multi-dose injectable aqueous parenteral pharmaceutical composition comprising GLP-1 and phenol in that: The fact pattern of instant application is the same as OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385 (Fed. Cir. 2019); none of the cited references shows a GLP-1(7-36) composition would be stable in the presence of phenol; and not all compositions comprising GLP-1 and phenol disclosed in instant specification exhibit long-term stability.
11. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant’s arguments about instant rejection, the Examiner agrees that none of the cited references individually teaches or suggests the multi-dose injectable aqueous parenteral pharmaceutical composition recited in instant claims 1, 3 and 5; and none of the cited references anticipates the multi-dose injectable aqueous parenteral pharmaceutical composition recited in instant claims 1, 3 and 5. However, the Examiner would like to point out that instant claims 1, 3 and 5 are rejected under 35 U.S.C. 103 (obviousness type); and the rejection is based on the combined teachings of Holmquist et al, Izutsu, Rinella Jr., Todd et al and Föger 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 reasonable expectation of success: The Examiner would like to point out that as stated in the previous office action, the fact pattern of instant application is very different from OSI Pharm., LLC v. Apotex Inc. for the following reasons:
First, as explicitly stated in Applicant’s arguments/remarks, it is well known in the cancer treatment art, non-small cell lung cancer (NSCLC) is extremely difficult to treat, with an over 99.5% rate of failure for drugs entering Phase II clinical studies. In the instant case, the Examiner understands that US patent 5705483 A (filed on 1995 and issued in 1998, cited by Applicant) expresses some concerns about the long-term stability of GLP-1 formulation. However, the instant application is filed on 7/31/2014. Between 1995 (the filing date of US patent 5705483 A) and 2014 (the filing date of instant application), many different stable aqueous formulations comprising GLP-1 have been successfully developed and are known in the art, like those disclosed in Holmquist et al, Rinella Jr., Ludvigsen et al (US 2010/0173844 A1, cited and enclosed in the previous office actions), Cherif-Cheikh et al (US 2010/0087365 A1, cited and enclosed in the previous office actions) and many others. Therefore, in the instant case, considering the state of art regarding a stable aqueous formulation comprising GLP-1, the reasoning in OSI Pharm., LLC v. Apotex Inc. would NOT apply to instant rejection.
Second, in terms of the so-called well-known stability issue of phenol on GLP-1 stability firmly believed by Applicant, as stated in the previous office actions, the Examiner understands that the instant specification discusses phenol might not be the ideal preservative for certain peptides/proteins in certain types of formulation (see the paragraph bridging pages 2 and 3 of instant specification). And it appears to the Examiner that the so-called well-known stability issue of phenol is partially based on Kirsch et al (Journal of Parenteral Science & Technology, 1993, 47, pages 155-160, cited and enclosed in the previous office actions). However, the Examiner would like to point out that Kirsch et al explicitly teach the effect of phenol on the stability of human growth hormone (hGH) is dose-dependent; and in comparison to solution comprising hGH, hGH aggregation due to the presence of phenol more likely happens after freeze-dying, for example, page 157, Table II and Figure 2; and page 158, Table III. Therefore, in the instant case, in view of the teachings of Kirsch et al as a whole, one of ordinary skilled in the art would understand and reasonably expect that phenol at a proper concentration would not affect the stability of a peptide and/or protein in an aqueous parenteral pharmaceutical composition.
Third, it is well known in the art that phenol can be a preservative in multi-dose injectable aqueous parenteral pharmaceutical composition comprising GLP-1 or analog thereof such as GLP-1(7-36), as shown in Rinella Jr., Ludvigsen et al (US 2010/0173844 A1, cited and enclosed in the previous office actions), Cherif-Cheikh et al (US 2010/0087365 A1, cited and enclosed in the previous office actions) and many others. The Examiner understands that phenol at a concentration of 0.5% (w/v) (equals to 5 mg/ml) is used in the working examples in the cited Rinella Jr. reference. However, in the instant case, as stated in Section 9 above, Rinella Jr. explicitly teaches in multi-dose injectable aqueous formulation comprising GLP-1 or analog or derivative thereof such as GLP-1(7-36), the more highly preferred preservative is phenol; the total concertation of preservative is preferably between about 1 mg/mL and 10 mg/mL; and the concentration of preservative is that required to maintain preservative effectiveness, which, in turn, may depend on the preservative, its solubility, and the temperature and the pH of the formulation. Furthermore, the instant claimed concentration of phenol as a pharmaceutically acceptable preservative (about 1.5 mg/mL to 3 mg/mL) overlaps and/or lies inside ranges disclosed by the prior art (1-10 mg/mL taught in both Izutsu and Rinella Jr.), the MPEP states that “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…” (see MPEP § 2144.05 I). In addition, as stated in the previous office action, in view of the teachings of Rinella Jr. on column 1, lines 50-56, one of ordinary skilled in the art would understand and reasonably expect that each of the parameters, such as choice of preservative, buffer, ionic strength, pH, temperature and other excipients, needs to/should be optimized to obtain a stable peptide/protein formulation.
Fourth, with regards to Applicant’s arguments based on GLP-1 compositions NOs: 35, 41 and 55-62 disclosed in instant specification, as stated in the previous office action, the Examiner would like to point out that none of these GLP-1 compositions is within the scope of instant claimed multi-dose injectable aqueous parenteral pharmaceutical composition. It is unclear to the Examiner how and/or why these compositions disclosed in instant specification are relevant to instant rejection. Furthermore, it appears to the Examiner that Applicant is required absolute predictability, which is not the standard for rejection under 35 U.S.C. 103.
Taken all these together, in the instant case, considering the state of art regarding phenol as a preservative in multi-dose injectable aqueous parenteral pharmaceutical composition comprising GLP-1 or analog thereof such as GLP-1(7-36), the state of art regarding stable aqueous formulation comprising GLP-1 or analog thereof such as GLP-1(7-36), and in view of the combined teachings of the cited prior art references as set forth in Section 9 above, a person of ordinary skilled in the art would have a reasonable expectation of success to develop the composition recited in instant claims 1, 3 and 5. And 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 Kirsch et al, Ludvigsen et al and Cherif-Cheikh et al references are cited only for the purpose of rebutting Applicant’s arguments, therefore, they are not cited as prior art reference.
12. Please note: during the search for the elected species, prior art was found for the non-elected species of insulinotropic peptide.
Claims 1, 3 and 5 remain rejected under 35 U.S.C. 103 as being unpatentable over Cherif-Cheikh et al (US 2010/0087365 A1, cited and enclosed in the previous office actions) in view of Izutsu (Therapeutic proteins, methods and protocols, Humana press, edited by C. Mark Smales and David C. James, 2005, pages 287-292, cited and enclosed in the previous office actions), Toda et al (US 2009/0105130 A1, cited and enclosed in the previous office actions) and Föger (US 2011/0293714 A1, cited and enclosed in the previous office actions).
The instant claims 1, 3 and 5 are drawn to a multi-dose injectable aqueous parenteral pharmaceutical composition comprising glucagon-like peptide 1 (GLP-1), mannitol, propylene glycol, phenol, and a pharmaceutically acceptable buffer salt solution of sodium acetate-acetic acid (NaAc-HAc), wherein: the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2; the GLP-1 is present at a concentration of 0.1 mg/mL to 20 mg/mL; phenol is present at a concentration of about 1.5 mg/mL to 3 mg/mL; and the GLP-1 is GLP-1(7-36).
Cherif-Cheikh et al, throughout the patent, teach a multi-dose injectable aqueous parenteral pharmaceutical composition comprising insulinotropic peptide hGLP-1(7-36)-NH2 (one type of GLP-1(7-36)) or analog thereof, a pharmaceutically acceptable isotonic agent, phenol as a pharmaceutically acceptable preservative, surfactant as a pharmaceutically acceptable dissolution enhancer, and sodium acetate-acetic acid (NaAc-HAc) as a pharmaceutically acceptable buffer salt solution; wherein the peptide compound is present at a concentration of about 0.00001-500 mg/mL, preferable about 0.0001-10 mg/mL, the preservative is present at a concentration from 0.01 mg/mL to 50 mg/mL, the isotonic agent is present at a concentration from 0.01 mg/mL to 50mg/mL, and the composition has a pH from 3.0 to 8.0, and preferably a pH from 4.0 to 6.0, for example, Abstract; page 1, paragraphs [0002], [0004], [0007] and [0008]; page 2, paragraph [0016] to page 3, paragraph [0038]; page 3, paragraph [0044]; page 6, paragraphs [0080] and [0085]; and claims 1, 6, 8-12, 15, 17, 18 and 22. It reads on phenol as the elected species of preservative and NaAc-HAc as the elected species of buffer salt solution. It meets the limitations of GLP-1(7-36), phenol, and sodium acetate-acetic acid (NaAc-HAc) recited in instant claim 1. Cherif-Cheikh et al further teach the dosage of the insulinotropic peptide such as hGLP-1(7-36)-NH2 in the formulation may be varied; the selected dosage depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the dosage is normally determined by the attending physician, for example, page 6, paragraph [0085].
The difference between the reference and instant claims 1, 3 and 5 is that the reference does not explicitly teach the dosages recited in instant claims 1, 3 and 5; the pH, mannitol and propylene glycol recited in instant claim 1; mannitol as the elected species of isotonic agent; and propylene glycol as the elected species of dissolution enhancer.
However, Izutsu, throughout the literature, teaches that for peptide/protein formulation, polyol such as mannitol can be added at a concentration of 10-100 mg/ml for tonicity modification to avoid irritation at the administration site, for example, page 288, Table 2. It reads on mannitol as the elected species of isotonic agent. Izutsu further teaches that for peptide/protein formulation, surfactant such as Tween-40 and Tween-80 at a concentration of less than 1 mg/ml can be added as solubilizer, stabilizer and aggregation inhibitor, for example, page 288, Table 2. Izutsu also teaches that for peptide/protein formulation, preservative such as phenol can be added at a concentration of 1-10 mg/ml for antimicrobial preservation, for example, page 288, Table 2. It reads on phenol as the elected species of preservative.
And in the instant case, the instant claimed concentration of phenol as a pharmaceutically acceptable preservative (about 1.5 mg/mL to 3 mg/mL) overlaps and/or lies inside ranges disclosed by the prior art (1-10 mg/mL taught in Izutsu and 0.01 mg/mL to 50 mg/mL taught in Cherif-Cheikh et al), the MPEP states that “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…” (see MPEP § 2144.05 I).
Furthermore, Todd et al teach propylene glycol as a dissolution enhancer for peptide/protein formulation, for example, page 1, paragraph [0014]; page 2, paragraphs [0022], [0043] and [0044]; and page 3, paragraph [0053]. It reads on propylene glycol as the elected species of dissolution enhancer.
In addition, Föger teaches that propylene glycol as a dissolution enhancer is biocompatible even at high dosages and has a high solvent capacity for GLP-1 compounds, for example, page 7, paragraph [0082]. It reads on propylene glycol as the elected species of dissolution enhancer.
And, one of ordinary skilled in the art would have been motivated to optimize the concentrations of hGLP-1(7-36)-NH2, mannitol and phenol in the composition and the pH of the composition, since Cherif-Cheikh et al explicitly teach the dosage of the insulinotropic peptide such as hGLP-1(7-36)-NH2 in the formulation may be varied; the selected dosage depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the dosage is normally determined by the attending physician. Furthermore, it is the normal desire of scientists or artisans to improve upon what is already generally known. In addition, 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 of Cherif-Cheikh et al, Izutsu, Toda et al and Föger with routine optimization to develop a multi-dose injectable aqueous parenteral pharmaceutical composition comprising hGLP-1(7-36)-NH2 (one type of GLP-1(7-36)), mannitol as a pharmaceutically acceptable osmotic agent at a concentration of 10 mg/mL to 100 mg/mL, phenol as a pharmaceutically acceptable preservative at a concentration of about 1.5 mg/mL to 3 mg/mL, propylene glycol as a pharmaceutically acceptable dissolution enhancer, and NaAc-HAc as a pharmaceutically acceptable buffer salt solution; wherein the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2, and the hGLP-1(7-36)-NH2 is present at a concentration of 0.1 mg/mL to 20 mg/mL.
One of ordinary skilled in the art would have been motivated to combine the teachings of Cherif-Cheikh et al, Izutsu, Toda et al and Föger with routine optimization to develop a multi-dose injectable aqueous parenteral pharmaceutical composition comprising hGLP-1(7-36)-NH2 (one type of GLP-1(7-36)), mannitol as a pharmaceutically acceptable osmotic agent at a concentration of 10 mg/mL to 100 mg/mL, phenol as a pharmaceutically acceptable preservative at a concentration of about 1.5 mg/mL to 3 mg/mL, propylene glycol as a pharmaceutically acceptable dissolution enhancer, and NaAc-HAc as a pharmaceutically acceptable buffer salt solution; wherein the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2, and the hGLP-1(7-36)-NH2 is present at a concentration of 0.1 mg/mL to 20 mg/mL, because Izutsu teaches that for peptide/protein formulation, polyol such as mannitol can be added at a concentration of 10-100 mg/ml for tonicity modification to avoid irritation at the administration site. Izutsu further teaches that for peptide/protein formulation, surfactant such as Tween-40 and Tween-80 at a concentration of less than 1 mg/ml can be added as solubilizer, stabilizer and aggregation inhibitor. Izutsu also teaches that for peptide/protein formulation, preservative such as phenol can be added at a concentration of 1-10 mg/ml for antimicrobial preservation. And in the instant case, the instant claimed concentration of phenol as a pharmaceutically acceptable preservative (about 1.5 mg/mL to 3 mg/mL) overlaps and/or lies inside ranges disclosed by the prior art (1-10 mg/mL taught in Izutsu and 0.01 mg/mL to 50 mg/mL taught in Cherif-Cheikh et al), the MPEP states that “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…” (see MPEP § 2144.05 I). Todd et al teach propylene glycol as a dissolution enhancer for peptide/protein formulation. Föger teaches that propylene glycol as a dissolution enhancer is biocompatible even at high dosages and has a high solvent capacity for GLP-1 compounds. Furthermore, one of ordinary skilled in the art would have been motivated to optimize the concentrations of hGLP-1(7-36)-NH2, mannitol and phenol in the composition and the pH of the composition, since Cherif-Cheikh et al explicitly teach the dosage of the insulinotropic peptide such as hGLP-1(7-36)-NH2 in the formulation may be varied; the selected dosage depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the dosage is normally determined by the attending physician. And it is the normal desire of scientists or artisans to improve upon what is already generally known. In addition, 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 Cherif-Cheikh et al, Izutsu, Toda et al and Föger with routine optimization to develop a multi-dose injectable aqueous parenteral pharmaceutical composition comprising hGLP-1(7-36)-NH2 (one type of GLP-1(7-36)), mannitol as a pharmaceutically acceptable osmotic agent at a concentration of 10 mg/mL to 100 mg/mL, phenol as a pharmaceutically acceptable preservative at a concentration of about 1.5 mg/mL to 3 mg/mL, propylene glycol as a pharmaceutically acceptable dissolution enhancer, and NaAc-HAc as a pharmaceutically acceptable buffer salt solution; wherein the aqueous parenteral pharmaceutical composition has a pH of 3.6 to 4.2, and the hGLP-1(7-36)-NH2 is present at a concentration of 0.1 mg/mL to 20 mg/mL.
Response to Applicant's Arguments
13. Applicant fails to present any argument about instant rejection. Therefore, the rejection is deemed proper and is hereby maintained.
Conclusion
All claims are drawn to the same invention claimed in the application prior to the entry of the submission under 37 CFR 1.114 and could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LI N KOMATSU whose telephone number is (571)270-3534. The examiner can normally be reached Mon-Fri 8am-4pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached on 5712707430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LI N KOMATSU/Primary Examiner, Art Unit 1658