DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Claims 59-65 (Group II) and 72 and 75-81 (Group III) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election of Group I was made without traverse in the reply filed on December 3, 2024.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 52-53, 57-58, 66, 70-71, 86-88, 91, and 93 are rejected under 35 U.S.C. 103 as being unpatentable over Prestrelski et al. (US 2017/0087215 A1) in view of Wang et al. (US 2005/0009739 A1).
Scope and contents of the prior art
Independent claim 52 is drawn to a storage stable sustained release formulation comprising five components: (a) a therapeutic peptide containing one or more aspartic acid and/or histidine residues; (b) a divalent salt of zinc, functioning as a sustained release modifier, wherein the ratio of zinc : peptide is 4:1 or 8:1; (c) DMSO polar aprotic solvent; (d) trehalose dihydrate; and (e) mannitol.
Prestrelski et al. teach stabilizing formulations of a therapeutic peptide in a polar aprotic solvent such as DMSO by adding an ionization stabilizing excipient such as a mineral acid (¶ [0010]-[0014]). Prestrelski et al. teach that protonation of ionogenic residues in the peptide by the ionization stabilizing excipient confers an overall positive charge on the peptide. Electrostatic repulsions between positively charged peptide molecules inhibit aggregation and gelation, thereby stabilizing the peptide in the polar aprotic solvent (¶ [0054]).
Regarding claim 52, part (a), Prestrelski et al. teach that the therapeutic peptide may be glucagon, pramlintide, insulin, leuprolide, an LHRH agonist, parathyroid hormone (PTH), amylin, botulinum toxin, hematide, angiotensin(1-7), an amyloid peptide, cholecystikinin, a conotoxin, a gastric inhibitory peptide, an insulin-like growth factor, a growth hormone releasing factor, an anti-microbial factor, glatiramer, glucagon-like peptide-1 (GLP-1), a GLP-1 agonist, or exenatide, preferably glucagon or a glucagon analog or a glucagon peptidomimetic (¶ [0018]; Example 4). These peptides have one or more ionogenic residues that can be protonated by a mineral acid. Prestrelski et al. teach that the ionization stabilizing excipient improves stability by protonating an ionogenic amino acid residue (¶ [0055]).
Regarding claim 52, part (c), Prestrelski et al. teach that the polar aprotic solvent is DMSO (¶ [0013], [0054]; Example 4).
Regarding claim 52, part (d), Prestrelski et al. teach that the formulation may further comprise suitable sugars for stabilizing excipients such as trehalose (¶ [0073]).
Regarding claim 52, part (e), Prestrelski et al. teach that the formulation may further comprise suitable sugar alcohols (also referred to as polyols) for stabilizing excipients such as mannitol (¶ [0073]; Example 4).
Regarding claim 52, wherein clause regarding stability, Prestrelski et al. teach solutions of 5 mg/mL glucagon in DMSO, 3.2 mM of added HCl, and 5.5% (w/v) mannitol were stable at room temperature (22-23° C) for 6 months, as assessed by RP-HPLC (Example 4; Table 5).
Differences between the prior art and the claims at issue
Prestrelski et al. do not teach the structural component of the composition presented in claim 52, part (b), the zinc salt, wherein the ratio of zinc : peptide is 4:1 or 8:1. Prestrelski et al. discloses but does not reduce to practice part (d) trehalose. Prestrelski et al. are silent regarding the functional limitation presented in claim 52 regarding sustained release.
Level of ordinary skill in the pertinent art
The prior art teaches that therapeutic peptides can be stabilized in organic solvents by divalent metal ions. Wang et al. teach stabilized formulations of therapeutic peptides comprising a histidine residue (¶ [0007], [0041], [0045). The peptides are dissolved in a polar aprotic organic solvent, preferably DMSO, and stabilized by a zinc salt, acid, or both (¶ [0007]-[0008], [0025]). Wang et al. teach that adding zinc yields a chelate complex between the zinc and histidine in the peptide, which inhibits peptide degradation and stabilizes the formulation (¶ [0041]). Wang et al. predict that a divalent zinc salt can stabilize any of the following peptides containing at least one histidine in DMSO in an analogous manner: vasoactive intestinal peptide, glucagon, glucagon-like peptides, growth hormone releasing factor, secretin, helodermin, exendin-4, adrenocorticotropic hormone, angiotensins, renin substrate tetradecapeptide, natriuretic peptides, gastrointestinal peptides, luteinizing hormone releasing hormone, melanocyte stimulating hormone, neurotensin, parathyroid hormone and insulin (¶ [0045]-[0046]).
Consideration of objective evidence
There is no evidence in the instant specification that the difference between the instant claims and the Prestrelski et al. reference, namely the presence of the divalent zinc salt and the addition of trehalose, has an unexpected effect on the claimed composition in view of the art. Regarding the divalent salt, Wang et al. predicts that salts such as ZnCl2 increase stability of peptides containing at least one histidine residue in DMSO (¶ [0041], [0045]). Wang et al. predicts that a ratio of zinc : peptide above 0.1 will be effective and reduces to practice 2:1 (¶ [0027]).1 Regarding trehalose, Prestrelski et al. predicts that adding trehalose increases stability of peptides in DMSO and that stabilizing excipients can be combined (¶ [0073]).
Obviousness Rationale: MPEP 2143(I)(A): Combining prior art elements according to known methods to yield predictable results
It would have been obvious to combine the ZnCl2 in the stabilized peptide DMSO formulations taught by Wang et al. with the stabilized peptide DMSO formulations containing HCl and mannitol taught by Prestrelski et al. and to further combine the combination with a second stabilizing excipient trehalose taught by Prestrelski et al. Wang et al. teach that the ratio of zinc to peptide is above 0.1, which contains with the claimed ratios 4:1 or 8:1 (¶ [0008]). Wang et al. reduce to practice a ratio of 2:1 (¶ [0027]),1 which is close to the claimed ratio. Wang et al. teach that the ratio can be optimized through routine experimentation to optimize stability (¶ [0035], [0042]). The resulting composition would comprise elements (a)-(e), satisfying all of the structural limitations of claim 52 and the active step of mixing these elements in claim 66. Given that all of the structural limitations of the claim would be met, the functional limitations for stability and sustained release recited in claims 52 and 66 would also be met. One of ordinary skill in the art would recognize that Prestrelski et al. and Wang et al. teach known methods for stabilizing therapeutic peptides in DMSO by adding excipients including mineral acids, ZnCl2, mannitol, and trehalose to improve stability. One of ordinary skill in the art would recognize that in the resulting combination, the therapeutic agent would function as the active biological agent as taught by Prestrelski et al. and Wang et al., the mineral acid would stabilize the therapeutic agent by protonating the ionogenic residues as taught by Wang et al., the zinc would stabilize the therapeutic agent by chelating histidine residues as taught by Wang et al., the mannitol and trehalose would function as a stabilizer as taught by Prestrelski et al. and the DMSO would function as the non-aqueous, stabilizing solvent as taught by Prestrelski et al. and Wang et al. One of ordinary skill in the art would recognize that the effect of adding the ZnCl2 taught by Wang et al. to the formulation taught by Prestrelski et al. would have a predictable effect on stability given that Wang et al. demonstrate that ZnCl2,can be used as a formulation excipient to stabilize a peptide containing at least one histidine in an organic solvent (¶ [0041], [0045]) and Prestrelski et al. teach the same peptides having ionogenic residues (¶ [0018]). The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art.
With respect to claims 53 and 86, Prestrelski et al. teach that the therapeutic peptide may be glucagon, pramlintide, insulin, leuprolide, an LHRH agonist, parathyroid hormone (PTH), amylin, botulinum toxin, hematide, angiotensin(1-7), an amyloid peptide, cholecystikinin, a conotoxin, a gastric inhibitory peptide, an insulin-like growth factor, a growth hormone releasing factor, an anti-microbial factor, glatiramer, glucagon-like peptide-1 (GLP-1), a GLP-1 agonist, or exenatide, preferably glucagon or a glucagon analog or a glucagon peptidomimetic (¶ [0018]; Example 4). These peptides have one or more histidine residues that can be protonated by a mineral acid.
Wang et al. the therapeutic agent is a peptide such as vasoactive intestinal peptide (VIP), glucagon, glucagon-like peptides, growth hormone releasing factor (GRF), secretin, helodermin, exendin-4, adrenocorticotropic hormone, angiotensins, renin substrate tetradecapeptide, natriuretic peptides, gastrointestinal peptides, luteinizing hormone releasing hormone, melanocyte stimulating hormone, and neurotensin, and parathyroid hormone (paragraph [0045]) or insulin (paragraph [0046]). These peptides have one or more histidine residues that can be protonated by a mineral acid and/or coordinated by zinc.
With respect to claims 57-58 and 70-71, Wang et al. teaches zinc salts, ZnCl2 (paragraph [0045]), and which one of ordinary skill in the art would recognize includes zinc salts formed with other pharmaceutically-recognized anions such as sulfate.
With respect to claims 87-88, Wang et al. teach concentrations of peptide that fall within the claimed range about 0.1 mg/mL to about 500 mg/mL and about 1 mg/mL to about 100 mg/mL, for example 300 mg/ml (Figure 4), 20 mg/ml (Figure 5) and a range that overlaps with the claimed ranges, above 0.1 mg/ml (claim 16).
With respect to claims 91 and 93, Wang et al. teach that the stabilizing excipients including mannitol and trehalose are present in the formulation in an amount that is about, at most, or at least 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% (w/v) (¶ [0073]), which includes the claimed concentrations.
Response to Arguments
Applicant's arguments filed March 6, 2026, have been fully considered but they are not persuasive.
Applicant traverses the rejection on the grounds that Wang reduces to practice a ratio of 2:1 not 5:1. Reply pages 6-8. Applicant is correct that the prior art ratio is 2:1 not 5:1 as asserted in the Office action, owing to an inadvertent error in the molecular weight of SEQ ID NO: 1 of Wang et al. However, this argument on its own is not persuasive because the rationale of the rejection is unchanged. Wang et al. teach that the ratio of zinc to peptide is in the range “above 0.1” (¶ [0008]), which contains the claimed ratios 4:1 and 8:1. Wang et al. reduce to practice a ratio of 2:1 (¶ [0027]),1 which is close to the claimed ratio 4:1. One of ordinary skill in the art would predict that adding the ZnCl2 taught by Wang et al. would improve stability of the formulation taught by Prestrelski et al. because these references teach the same histidine-containing peptides and because Wang et al. demonstrate that ZnCl2 improves the stability of histidine-containing peptides (Wang et al. ¶ [0041], [0045]; Prestrelski et al. ¶ [0018]). One of ordinary skill would optimize the ratio of zinc to peptide through routine experimentation because Wang et al. teach that this ratio is a result-effective variable for stability (¶ [0035], [0042]).
Next Applicant responds to the argument in the previous Office action regarding the evidence in Fitch declaration being limited to a single species, glucagon. Reply pages 9-10. Applicant’s arguments in this section are acknowledged but are insufficient to overcome the rejection in view of the additional issues raised in that action, which Applicant has not addressed.
The declaration under 37 CFR 1.132 filed November 25, 2025, by Martin Donovan, Ph.D. (hereafter “the Donovan declaration”) is insufficient to overcome the rejection of the claims. MPEP § 716.02(c)(II) states that expected beneficial results are evidence of obviousness. In the instant case, the Donovan declaration describes evidence from Example 1 of the specification showing that divalent zinc salts at the claimed ratios promote peptide stability in DMSO and attributes the effect to the formation of a coordination complex of histidine residues and zinc (Donovan Declaration ¶ 14). This observed effect and the proposed mechanism of stabilization is expected, not unexpected, in view of Wang et al., which states in ¶ [0041]:
The results show that ZnCl2 stabilized PACAP 66 in DMSO, while MgCl2 and CaCl2 did not. This suggests that metal ions do not stabilize PACAP 66 simply by ionic interactions. Therefore, we proposed that zinc and PACAP 66 form a chelate complex via the N-terminal histidine residue, which hinders its own degradation. To prove our hypothesis, we measured the NMR spectrum of PACAP 66 in DMSO in the absence and presence of 1 mM ZnCl2 (FIG. 8). The most dramatic difference in the spectrum in the presence of 1 mM ZnCl2 is the disappearance of the histidine H2 and H4 signals in the broad amide background. This clearly suggests an interaction Of ZnCl2 with the terminal histidine residue. On the other hand, the spectrum of PACAP 66 in D2O is essentially the same in the absence or presence of ZnCl2 (data not shown). Therefore, these results indicate that peptide-Zn interaction is present only in an organic solvent, not in an aqueous solution, and explain why zinc oxide at 10 mM did not stabilize PACAP 66 in an aqueous solution (FIG. 1).
Given that the effect of divalent zinc salts on glucagon stability in DMSO described in the Donovan declaration is the same as that reported by Wang et al. for PACAP 66 stability in DMSO, the evidence relied upon is expected, not unexpected, in view of the prior art.
The declaration under 37 CFR 1.132 filed November 25, 2025, by Martin Donovan, Ph.D. (hereafter “the Donovan declaration”) is insufficient to overcome the rejection of the claims. MPEP § 716.02(d)(II) states: To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). In the instant case, Examples 1 and 2 include formulations with ratios of 4:1 and 8:1 as well as of 1:1 and 16:1. However, there is no stability data presented for the compositions with ratios 1:1 and 16:1 (A-3 and A-6). Therefore, it is not clear from the Donovan declaration whether the claimed ratios confer different effects than the unclaimed ratios. Given that all of these ratios are within the prior art range of above 0.1: 1, and close to the prior art ratio reduced to practice, 2:1, one of ordinary skill in the art would expect all to work effectively.
For these reasons, the rejection is maintained.
Claims 82-85 are rejected under 35 U.S.C. 103 as being unpatentable over Prestrelski et al. (US 2017/0087215 A1) and Wang et al. (US 2005/0009739 A1), as applied to claims 52-53, 57-58, 66, 70-71, 86-88, 91, and 93 above, in further view of Sabharwal et al. (US 2019/0083578 A1).
Neither Prestrelski et al. nor Wang et al. teach the addition of a polymer to the formulation for sustained-release.
Sabharwal et al. teach non-aqueous ionization stabilized compositions of glucagon comprising a the polar aprotic solvent DMSO, the ionization stabilizing excipient HCl, and the stabilizing excipient mannitol (¶ [0096]-[0105]; claims 1-22). One of ordinary skill in the art would recognize that these compositions are related to those taught by Prestrelski et al. and Wang et al.
Sabharwal et al. further teach that the compositions may contain a pharmaceutically acceptable polymer (e.g. PLGA, PLA) in an amount effective to slow the release of the therapeutic agent(s) from said formulation upon administration via injection into the epidermal, dermal or subcutaneous layer of an animal (¶ [0147]).
Response to Arguments
Applicant's arguments filed March 6, 2026, have been fully considered but they are not persuasive.
Applicant traverses the rejection on the grounds that Sabharwal fails to cure the deficiencies of Prestrelski and Wang because it does not teach divalent zinc salts at all. Reply page 10. This argument is not persuasive because it attacks the references individually. Sabharwal is relied upon to teach polymer excipients.
For these reasons, the rejection is maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
1 Wang et al. teach 2 mg/ml PACAP 66 peptide, 1 mM ZnCl2 in DMSO. Based on the sequence of PACAP 66 in Wang et al., SEQ ID NO: 1, the molecular weight is 4283.7134 g/mol (corrected in response to the error raised by Applicant on March 6, 2026). The concentration of PACAP 66 is: 2 mg PACAP 66/ml x g/1000 mg x mol/4238.7134 g x 1000 ml/L x 1000 mmol/mol = 0.467 mmol PACAP 66/L = 0.467 mM PACAP 66. The ratio of ZnCl2 : PACAP 66 peptide is 1/0.467 = 2:1.
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