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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/02/2026 has been entered.
Status of the application
Receipt of applicant’s remarks and claim amendments filed on 02/02/2026 are acknowledged.
In light of claim amendments, the previous 112(b) rejection is withdrawn.
However, applicants’ arguments for the previous 103 rejection are found not persuasive. Accordingly, the previous rejection is maintained and modified to address claim amendments. Please see the examiners response to applicants below.
In addition, new 102 and 103 rejections are made in this office action.
Response to Arguments
Applicants main argument is that Topp reports stability data extending no more than approximately 15 days. Topp at paragraph [0080], and DiMarchi merely states that "the methionine residue present at position 27 of the native peptide is changed to leucine or norleucine to prevent oxidative degradation of the peptide," and references stability improvements measured over no more than approximately seven days. Thus, nothing in the cited art teaches or suggests peptides or compositions that remain oxidatively stable for months or that exhibit less than 10% oxidation after three months at 30 °C in PBS and/or EDTA as expressly required by the claims.
In the teachings of Topp, the 15 days associated with only ‘phosphorylated cites’, but not in combination with the ‘replacement of Met27 with norleucine’. It appears that DiMarchi does not say ‘no more than seven days’ in their disclosure.
However, see below, the modified previous rejection and newly added 102 and 103 rejections, which addresses applicants comments.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
(i) Claims 6-7 and 9-14 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Topp (US 2018/0298076 A1).
Claims require one of recited (a) or (b) or (c). The following rejection is based on the recited option (b) in the claims.
For claim 6:
Topp discloses a modified glucagon, wherein a glucagon molecule includes one or more modified amino acids to result in the glucagon molecule being soluble at a substantially neutral pH, wherein the amino acid sequence of glucagon is HSQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO. 1), wherein glucagon is phosphorylated at Thr5 or Ser8 [see Table 3].
Topp further exemplified their modified glucagon a sample containing glucagon, phospho-Ser2-, phospho-Thr5- or phospho-Ser8-glucagon at 1.6 mg/mL in 3.2 mM HCl, 0.9% NaCl (w/v) (pH 2.5) were added to 1× phosphate buffer saline (PBS), pH 7.4. [see Example 1].
The above is interpreted as pharmaceutical composition or formulation [see cf. 0057].
Topp define their formulation as the formulation maintains the chemical and physical stability of the active pharmaceutical ingredient (e.g., phosphoglucagon) to within acceptable limits after an extended period of storage at the intended storage conditions of the product. In some embodiments, a stable formulation has less than 10% degradation over two years or less than 5% degradation over two years. [see 0034].
Topp further exemplified solutions of phosphoglucagons and their chemically stability when stored for ten days at 5°C, 23°C and 37°C, wherein phosphoglucagon samples were prepared in 50 mM sodium phosphate, pH 7.4 and stored at 5°C., 23°C. and 37°C, did not show any chemical degradation after 10 days of storage of phospho-Thr5-glucagon (FIG. 6A) and phospho-Ser8-glucagon (FIG. 6B). Enhanced mass spectra of intact phosphoglucagon (m/z=891.1609, z=+4) at time t=0 compared with samples stored at 5°C, 23°C and 37°C showed no chemical degradation after 10 days of storage. However, low levels of singly and doubly oxidized degradation products were observed for both phospho-Thr5- and phospho-Ser8-glucagon samples stored at 37°C for 15 days (FIGS. 7A and 7B). The figures show the enhanced mass spectra of intact phosphoglucagon (m/z=891.1609, z=+4) at time t=0 compared with samples stored for 15 days. Tandem mass spectrometric (MS/MS) analysis confirms that the site of oxidation is residue Met 27 for both phospho-Thr5-glucagon and phospho-Ser8-glucagon. Addition of antioxidants may prevent phosphoglucagon oxidation and improve the long-term storage stability of these peptides in solution.
In the above, no chemical degradation after 10 days of storage is interpreted as less than 10% oxidation after 3 months when pharmaceutical composition is store at 30oC.
For claim 7:
Topp discloses that the oxidation of Met27 and can be controlled with the addition of ethylene diamine tetraacetic acid (EDTA) [see 0021]. Topp further teaches that addition of antioxidants may prevent phosphoglucagon oxidation and improve the long-term storage stability of these peptides in solution [see 0080].
For claim 9-10:
Topp discloses that their composition is a prodrug of glucagon, wherein the functional group may be chemically or enzymatically cleaved [see 0011 and 0039].
For claim 11:
See For claim 7 above.
For claim 12:
Topp discloses PBS and EDTA in their compositions [see Example 1 and 0021].
For claim 13:
Topp discloses pH 7.4, which is along the lines of applicants definition of substantially neutral pH, which is “A substantially neutral pH includes a physiological neutral pH of about 7.4”.
For claim 14:
Topp discloses concentration of phospho-Ser2-, phospho-Thr5- or phospho-Ser8-glucagon at 1.6 mg/mL [see Example 1].
Accordingly, claims are fully anticipated.
(ii) Claims 6 and 13-14 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dimarchi (US 2012/0196804 A1).
Claims require one of recited (a) or (b) or (c). The following rejection is based on the recited option (a) in the claims.
For claim 6:
Dimarchi discloses the following sequence:
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[see SEQ ID NO:1].
The above sequence is identical to applicants SEQ ID NO:1.
Dimarchi further discloses that the Met residue present at position 27 of the native peptide is changed to Leu or Nle (norleucine) to prevent oxidative degradation of the peptide, and these modified sequences having improved solubility and stability, these are represented by the following disclosed sequences in the teachings of Dimarchi:
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[see abstract and page 4].
The above reads applicants claimed modified SEQ ID NO:1. The preventive oxidative degradation of the peptide is interpreted as or reads applicants ‘peptide exhibits less than 10% oxidation after 3 months when the pharmaceutical composition is stored at 30oC”.
Dimarchi further discloses that in accordance with one of their embodiments a pharmaceutical composition is provided comprising the novel glucagon peptides disclosed herein, and the pharmaceutical compositions comprise solutions that are sterilized and contained within various packages [see 0010]. The “solutions that are sterilized” is interpreted as a pharmaceutically acceptable carrier and the term ”comprising” is an open language and so, the composition can have additional components in it.
Dimarchi further discloses phosphate buffered saline solution with EDTA [0019 and 0082], which is nothing but modified peptide is soluble in the pharmaceutical acceptable carrier.
For claim 13:
Dimarchi discloses pH 7.4 [see 0058], which is along the lines of applicants definition of substantially neutral pH, which is “A substantially neutral pH includes a physiological neutral pH of about 7.4”.
For clam 14:
Dimarchi discloses various concentrations of their modified glucagon. For example, glucagonCys analog is dissolved in phosphate buffer saline at 5-10 mg/mL [see 0082].
Accordingly claims are fully anticipated.
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 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 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.
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.
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.
(i) Claims 6-14 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Dimarchi (US 2012/0196804 A1) in view of Topp (US 2018/0298076 A1).
For claim 6:
Dimarchi teaches the following sequence:
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[see SEQ ID NO:1].
The above sequence is identical to applicants SEQ ID NO:1.
Dimarchi further teaches that the Met residue present at position 27 of the native peptide is changed to Leu or Nle (norleucine) to prevent oxidative degradation of the peptide, and these modified sequences having improved solubility and stability, these are represented by the following disclosed sequences in the teachings of Dimarchi:
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[see abstract and page 4].
The above reads applicants claimed modified SEQ ID NO:1. The preventive oxidative degradation of the peptide is interpreted as or reads applicants ‘peptide exhibits less than 10% oxidation after 3 months when the pharmaceutical composition is stored at 30oC”.
Dimarchi further discloses that in accordance with one of their embodiments a pharmaceutical composition is provided comprising the novel glucagon peptides disclosed herein, and the pharmaceutical compositions comprise solutions that are sterilized and contained within various packages [see 0010]. The “solutions that are sterilized” is interpreted as a pharmaceutically acceptable carrier and the term ”comprising” is an open language and so, the composition can have additional components in it.
Dimarchi further teaches phosphate buffered saline solution with EDTA [0019 and 0082], which is nothing but modified peptide is soluble in the pharmaceutical acceptable carrier.
The difference is that Dimarchi is silent on phosphorylated peptide.
However, advantages of protein phosphorylation and its advantages are well established in the art. For example, see the following teachings of Topp:
Top teaches a modified glucagon, wherein a glucagon molecule includes one or more modified amino acids to result in the glucagon molecule being soluble at a substantially neutral pH, wherein the amino acid sequence of glucagon is HSQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO. 1), wherein glucagon is phosphorylated at Thr5 or Ser8 [see Table 3].
Topp further teaches that addition of a phosphate group on these residues can insert a charged and highly hydrophilic group into the core of a highly hydrophobic steric zipper, thus “opening” the zipper and inhibiting fibril formation. Moreover, the charged phosphate groups are expected to increase the solubility of the peptide, particularly at substantially neutral pH when the phosphate groups are in their fully ionized form. In the preferred embodiments, the computational models suggest that phosphorylation on, for example, Thr5 or Ser8 is very effective because those sites place the charge in the middle of the steric zipper, while, for example, phosphorylation at Ser2 may be less effective because the Ser2 side chain is not embedded in the zipper core. [See 0038-0041].
Therefore, one would be motivated to combine the teachings of Topp into the teachings of Dimarchi and arrive applicants claimed invention with a reasonable expectation of success.
For claim 7:
Dimarchi teach EDTA in the pharmaceutical compositions [see examples], wherein EDTA is an antioxidant. Topp also teaches that oxidation of Met27 and can be controlled with the addition of ethylene diamine tetraacetic acid (EDTA) and other formulation approaches known in the art [see 0021]. Topp further teaches that addition of antioxidants may prevent phosphoglucagon oxidation and improve the long-term storage stability of these peptides in solution [see 0080].
For claim 8:
Though Dimarchi silent on phosphorylation, as explained above, Topp teaches that one or more phosphorylated amino acids in an analog of glucagon [see Table 2]. Topp further explained that it is also observed that four residues (Ser2, Thr5, Ser8 and Tyr10) that are involved in the most frequent contacts can be phosphorylated [See 0038-0041].
For claim 9-10:
Though Dimarchi silent on phosphorylation, but Topp teaches that their composition is a prodrug of glucagon, wherein the functional group may be chemically or enzymatically cleaved. [see 0011 and 0039].
For claim 11:
As explained above, Dimarchi teach EDTA in the pharmaceutical compositions [see examples], wherein EDTA is an antioxidant. Topp teaches that oxidation of Met27 and can be controlled with the addition of ethylene diamine tetraacetic acid (EDTA) and other formulation approaches known in the art [see 0021].
For claim 12:
Dimarchi teaches phosphate buffered saline solution with EDTA [0019 and 0082].
Generally, differences in concentrations of components of a formulation will not support the patentability of subject matter encompassed by the prior art. Such formulations are results-effective variables which can be optimized. In in re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980), it was held that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As formulating optimal compositions for medicaments is routine in the art of pharmacology, the claims are considered to be prima facie obvious.
For claim 13:
Dimarchi teaches that their composition comprising glucagon peptide and pharmaceutically acceptable carrier wherein the pH of the composition is at a physiologically acceptable pH [see 58]. The physiologically acceptable pH is interpreted as neutral pH.
For claim 14:
Dimarchi teaches various concentrations of their modified peptide, which ranges from 5-10 mg/ml [0082], or 15.1 mg to 24.7 mg [see examples].
For claim 27:
See For claim 6 above.
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, applicants individual components in the composition and their advantages, were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to combine the art arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed pharmaceutical composition with a reasonable expectation of success.
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983).
(ii) Claims 6-14 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Topp (US 2018/0298076 A1) in view of Dimarchi (US 2012/0196804 A1).
For claim 6:
Topp teaches a modified glucagon, wherein a glucagon molecule includes one or more modified amino acids to result in the glucagon molecule being soluble at a substantially neutral pH, wherein the amino acid sequence of glucagon is HSQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO. 1), wherein glucagon is phosphorylated at Thr5 or Ser8 [see Table 3].
Topp further exemplified their modified glucagon a sample containing glucagon, phospho-Ser2-, phospho-Thr5- or phospho-Ser8-glucagon at 1.6 mg/mL in 3.2 mM HCl, 0.9% NaCl (w/v) (pH 2.5) were added to 1× phosphate buffer saline (PBS), pH 7.4. [see Example 1].
The above is interpreted as pharmaceutical composition or formulation [see cf. 0057].
Topp define their formulation as the formulation maintains the chemical and physical stability of the active pharmaceutical ingredient (e.g., phosphoglucagon) to within acceptable limits after an extended period of storage at the intended storage conditions of the product. In some embodiments, a stable formulation has less than 10% degradation over two years or less than 5% degradation over two years. [see 0034].
Topp further exemplified solutions of phosphoglucagons and their chemically stability when stored for ten days at 5°C, 23°C and 37°C, wherein phosphoglucagon samples were prepared in 50 mM sodium phosphate, pH 7.4 and stored at 5°C., 23°C. and 37°C, did not show any chemical degradation after 10 days of storage of phospho-Thr5-glucagon (FIG. 6A) and phospho-Ser8-glucagon (FIG. 6B). Enhanced mass spectra of intact phosphoglucagon (m/z=891.1609, z=+4) at time t=0 compared with samples stored at 5°C, 23°C and 37°C showed no chemical degradation after 10 days of storage. However, low levels of singly and doubly oxidized degradation products were observed for both phospho-Thr5- and phospho-Ser8-glucagon samples stored at 37°C for 15 days (FIGS. 7A and 7B). The figures show the enhanced mass spectra of intact phosphoglucagon (m/z=891.1609, z=+4) at time t=0 compared with samples stored for 15 days. Tandem mass spectrometric (MS/MS) analysis confirms that the site of oxidation is residue Met 27 for both phospho-Thr5-glucagon and phospho-Ser8-glucagon. Addition of antioxidants may prevent phosphoglucagon oxidation and improve the long-term storage stability of these peptides in solution.
In the above, no chemical degradation after 10 days of storage is interpreted as ‘less than 10% oxidation after 3 months when pharmaceutical composition is store at 30oC’.
Differences between Topp and instant claim(s) are as follows:
(i) Topp is silent on modified SEQ ID NO:1, wherein amino acid at position 27 is substituted with norleucine.
(ii) Topp is silent on that modified peptide exhibits less than 10% oxidation after 3 months when the pharmaceutical composition is stored at 30oC.
With regard to (i) and (ii) of above, Dimarchi cures these deficiencies, see below.
Dimarchi teaches the following sequence:
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[see SEQ ID NO:1].
The above sequence is identical to applicants SEQ ID NO:1.
Dimarchi further teaches that the Met residue present at position 27 of the native peptide is changed to Leu or Nle (norleucine) to prevent oxidative degradation of the peptide, and these modified sequences having improved solubility and stability, these are represented by the following disclosed sequences in the teachings of Dimarchi:
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[see abstract and page 4].
The above reads applicants claimed modified SEQ ID NO:1. The preventive oxidative degradation of the peptide is interpreted as or reads applicants ‘peptide exhibits less than 10% oxidation after 3 months when the pharmaceutical composition is stored at 30oC”.
Therefore, a skilled person in the art would be motivated to replace Met 27 with norleucine, to avoid external addition of antioxidant and also replacement increases solubility and stability, as evidenced from the teachings of Dimarchi.
For claim 7:
Topp teachs that the oxidation of Met27 and can be controlled with the addition of ethylene diamine tetraacetic acid (EDTA) [see 0021]. Topp further teaches that addition of antioxidants may prevent phosphoglucagon oxidation and improve the long-term storage stability of these peptides in solution [see 0080].
For claim 8:
Topp teaches that one or more phosphorylated amino acids in an analog of glucagon [see Table 2]. Topp further explained that it is also observed that four residues (Ser2, Thr5, Ser8 and Tyr10) that are involved in the most frequent contacts can be phosphorylated [See 0038-0041].
For claim 9-10:
Topp teaches that their composition is a prodrug of glucagon, wherein the functional group may be chemically or enzymatically cleaved [see 0011 and 0039].
For claim 11:
See For claim 7 above.
For claim 12:
Topp teaches PBS and EDTA in their compositions [see Example 1 and 0021].
For claim 13:
Topp teaches pH 7.4, which is along the lines of applicants definition of substantially neutral pH, which is “A substantially neutral pH includes a physiological neutral pH of about 7.4”.
For claim 14:
Topp teaches concentration of phospho-Ser2-, phospho-Thr5- or phospho-Ser8-glucagon at 1.6 mg/mL [see Example 1].
For claim 27:
See For claim 6 above.
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, applicants individual components in the composition and their advantages, were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to combine the art arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed pharmaceutical composition with a reasonable expectation of success.
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658