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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/23/2026 has been entered.
Claim Status
Claims 1, 5, 31, 36-41 and 46 are pending. Claim 1 was amended in the Reply filed 2/23/2026. Claims 36-41 and 46 remain withdrawn as directed to a non-elected invention. Claims 1, 5, and 31 are presently considered.
Election/Restrictions
Applicant’s election without traverse of Group I (products claims of original claims 1-5, 17-22, and 30-31) and the species identified below in the reply filed on 3/04/2024 was previously acknowledged.
The elected species was understood to be Formulation 3 of Example 4 (see, e.g., Spec. filed 3/25/2021 at 26 at line 28 to page 27 at line 1, Table 3 on page 30), wherein the species comprises 10 mg/mL ZP1848 (e.g., SEQ ID NO: 1, wherein R1 is H, Z1 is absent, X5 is Thr, X11 is Ala, Z2 is (K)6, and R2 is NH2), a pH of 7, 100 mM mannitol, 15 mM histidine, and also 3.15 mg/mL meta-cresol and 150 mM propylene glycol (see, e.g., Reply filed 3/04/2024 at 1; see also, Spec. filed 3/25/2021 at 26 at line 28 to page 27 at line 1, Table 3 on page 30). Accordingly, the structure of ZP1848 is understood to be is understood to be
HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2
In the response filed 2/23/2026, the claims were amended to exclude the originally elected species by excluding the component of propylene glycol. Per MPEP § 803.02(III)(A), examination has been extended to a non-elected species of liquid pharmaceutical formulation comprising 10 mg/mL ZP1848, a pH of 6.0 and 6.8, 100 mM mannitol, 15 mM histidine, and also 3.15 mg/mL meta-cresol. Following extensive search and examination, the non-elected species has been deemed obvious in view of the prior art as applied below.
Claims 36-41 and 46 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 was made without traverse in the reply filed on 3/04/2024.
During the search and examination of the originally elected species, art pertinent to other non-elected species was incidentally discovered. Although examination has not been extended beyond the non-elected species identified above per MPEP § 803.02, as a courtesy to the Applicant, this art has been applied below.
Claims 1, 5, and 31 are presently considered.
Related Applications
Examiner notes that US Application 17/276,252 and US Application 18/487,666 each pertain to highly similar subject matter.
Priority
The priority claim to EP18197750.5 (filed 9/28/2018) is acknowledged.
Information Disclosure Statement
The IDS filed 2/23/2026 is acknowledged and presently considered.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action.
Claim 1 is representative of the pending claim scope. Applicable claim interpretations are set forth below.
Regarding the preamble of claim 1, per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Accordingly, here the body of claim 1 is understood to recite a structurally complete invention, and therefore the preamble is deemed fully satisfied by prior art that satisfies the steps and structures recited in the body of the claim (see also MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”).
The claims recite intended use language at the recitation of each component (e.g., “as a preservative”, “buffer”, “non-ionic tonicity modifier”). As chemical activity is inherent, such activity is presumed fully satisfied if the recited component is present within the concentration range presently claimed.
The structure of ZP1848 (present in originally elected species) is understood to be the sequence of
HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2
This is a prior art structure, first taught and disclosed in WO2006/117565A1 (Nov. 9, 2006; Larsen et al.) as “1848” or [Gly2, Glu3, Thr5, Ser8, Leu10, Ala 11, 16, 24, 28]hGLP-2(1-33)-(Lys)6-NH2 (see, e.g., WO’565 at 20 at lines 39-40, 22 at lines 4-12, 42 at “1848”, claim 11, 14, passim).
The previously recited range of “20 mM to 300 mM” of propylene glycol is understood to be approximately equivalent to the range of ~1.522 g/mL to 22 g/mL1, wherein the MW of propylene glycol is 76.095 g/mol.
The interpretation of “about” was previously set forth on record (see, e.g., Action mailed 3/25/2024 at 7), and that interpretation is incorporated herein. The meaning of “about” is understood, for reasons of record, to mean at least ±20%. Accordingly, the ranges at claim 1 reciting “about 10 mg/mL” and “about 15 mM” are understood to encompass the ranges of at least 8-12 mg/mL and 12-18 mM, respectively.
The interpretations set forth in the Actions mailed 6/11/2025, 8/28/2024 and 3/25/2024 were not disputed with specificity in the Replies filed 9/11/2025, 1/23/2025 or 6/25/2024, respectively.
Additional claim interpretations are provided below.
Withdrawn Claim Rejections
Examiner notes that four rejections of record
The rejection of claims 1, 5, and 31 under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 8,163,696 B2 (cited in prior action) in view of Rowe et al. 2, WO2005/049061 A2 (cited in prior action), and US 7,411,039 B2 (cited in prior action) has been withdrawn as substantially cumulative over the rejection under 103 of instant claims 1, 5, and 31 in view of US 7,745,403 B2 in view of Rowe, WO2005/049061A2 and US 7,411,039 B2.
The rejection of claims 1, 5, and 31 under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 8,263,552 B2 (cited in prior action) in view of Rowe et al. 3, WO2005/049061 A2 (cited in prior action), and US 7,411,039 B2 (cited in prior action) has been withdrawn as substantially cumulative over the rejection under 103 of instant claims 1, 5, and 31 in view of US 7,745,403 B2 in view of Rowe, WO2005/049061A2 and US 7,411,039 B2.
The rejection of claims 1, 5, and 31 under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 9,125,882 B2 (cited in prior action) in view of Rowe et al. 4, WO2005/049061 A2 (cited in prior action), and US 7,411,039 B2 (cited in prior action) has been withdrawn as substantially cumulative over the rejection under 103 of instant claims 1, 5, and 31 in view of US 7,745,403 B2 in view of Rowe, WO2005/049061A2 and US 7,411,039 B2.
The rejection of claims 1, 5, and 31 under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 9,580,487 B2 (cited in prior action) in view of Rowe et al. 5, WO2005/049061 A2 (cited in prior action), and US 7,411,039 B2 (cited in prior action) has been withdrawn as substantially cumulative over the rejection under 103 of instant claims 1, 5, and 31 in view of US 7,745,403 B2 in view of Rowe, WO2005/049061A2 and US 7,411,039 B2.
New or Revised Claim Rejections as Necessitated by Applicant Amendment
Claim Rejections - 35 USC § 112(b)
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.
Claims 1, 5, and 31 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Amended claim 1 recites “the formulation comprising…” at line 1, but subsequently states “wherein the formulation consists of” at line five, which renders the claim scope indefinite as presently drafted, because it is unclear whether or not the liquid pharmaceutical multi-dose formulation is open-ended (i.e., “comprising”) or closed (i.e., “consisting of”). Here, close prior art exists as evidenced by the record (see, e.g., rejections under 35 USC 103 below), and therefore it is unclear what aspects are “open-ended” since the “formulation consists of” (a)-(e) as recited at claim 1. For example, it is unclear if the “comprising” language means that the GLP-2 analogue may be derivatized or not; if so, it is unclear how or at what position a derivative may be formed by conjugation. Accordingly, there is a substantial and material concern regarding what is or is not within the scope of the instant claim language since the formulation is defined as both open-ended and closed, within the same claim. For purposes of applying prior art, it is assumed that the claim language is closed, which is reasonable in view of Applicant arguments.
Claims 5 and 31 depend from claim 1, and fail to reconcile the indefiniteness of the base claim. Accordingly, claims 5 and 31 are also rejected as indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 5 depends from claim 1, which recites a “pH” range, which necessarily and inherently means that claim 1 requires an aqueous formulation as required to have a pH as claimed. Therefore, claim 5 is rejected as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
[Rejection 01]
Claims 1, 5, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over US 7,745,403 B2 (cited in previous action) in view of Rowe et al.6 and US 7,411,039 B2 (cited in previous action).
Claim Interpretation: The applicable claim interpretation has been set forth above in a separate section entitled “Claim Interpretations” above. Those interpretations and discussions are incorporated herein unless otherwise explicitly stated. Additional claim interpretations are discussed below.
The primary reference teaches and discloses a highly similar genus of compounds. Regarding the GLP-2 analog structure recited at instant claims 1 and 31, the primary reference claims methods necessitating the existence of pharmaceutical compositions comprising salts of SEQ ID NO: 34, wherein SEQ ID NO: 34 of the primary reference satisfies the GLP-2 structure of instant claim 1 wherein R1 is H, Z1 is absent, X5 is Serine, X11 is Ser, Z2 is (K)6, and R2 is NH2 (compare US’403 at claims 1-2, SEQ ID NO: 34 with instant claims 1-2 and “ZP1848”). Therefore, the specific GLP-2 analog of ZP1848 is a prior art structure. Regarding instant claims 1, 5, 31, and the concentrations of the GLP-2 analogue, L-histidine, mannitol, and the pH, the primary reference explicitly teaches, discloses, and directs artisans to utilize pharmaceutically acceptable compositions of the recited GLP-2 analog suitable for use in the recited methods (see, e.g., US’403 at claims 1-2); and specifically directs artisans to utilize pharmaceutical formulations comprising 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 100 mM to 230 mM, a pH of 6.7 to 7.3 in an aqueous solution (see, e.g., US’403 at col 29 at lines 3-34; see also id. at col. 28 at line 1 to col. 29 at 50) (see also MPEP § 2144.05(I), noting 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”). Regarding claims 1, 5, 31, and the presence of m-cresol, the primary reference explicitly teaches and discloses that the GLP-2 analogue formulations may comprise m-cresol (see, e.g., US’403 at col. 26 at lines 25-56, col. 25 at lines 35-55).
The disclosure of the primary reference differs from the instant claims as follows: although the primary reference discloses that the disclosed formulations may comprise m-cresol, the primary reference does not explicitly teach or disclose the usage of 3.15 mg/ml of meta-cresol as required by amended claim 1.
Regarding claims 1, 5, 31, and m-cresol: M-cresol was a well-known pharmaceutical excipient (see, e.g., Rowe at 203-205 and 592-594; see also US’039 at col. 28 at line 62 to col. 29 at line 55). M-cresol had known and expected utility and benefits, known concentration ranges typically utilized in peptide formulations, and had been taught and utilized in the GLP-2 pharmaceutical formulation arts.
Regarding m-Cresol:
M-cresol had known and predicted utility and benefits in peptide pharmaceutical formulations: Rowe explains that m-cresol (see, e.g., Rowe at 203 at §5) is utilized as an antimicrobial preservative (see, e.g., Rowe at 203 at §6, 204 at §10), is active below pH 9 and exhibits antimicrobial activity against gram-positive and gram negative bacteria, yeasts, and molds (see, e.g., Rowe at 203 at §6, 204 at §10). Rowe explains that “[s]ynergistic effects between cresol and other preservatives have been reported” in the art (see, e.g., Rowe at 204 at §10), and that m-cresol “is generally considered the least toxic of the three cresol isomers” (see, e.g., Rowe at 205 at §18). Rowe explains that m-Cresol can be used as an antimicrobial preservative in intramuscular, intradermal, and subcutaneous injections ” (see, e.g., Rowe at 205 at §7).
The commonly used range of m-cresol overlaps with the instantly claimed range: Rowe explains that m-cresol is typically utilized at 0.15-0.3% concentration in antimicrobial preservative in injectable pharmaceutical formulations (see, e.g., Rowe at 205 at §7). US’039 explains that preservatives, including m-cresol, may be included in GLP-2 pharmaceutical formulations at 0.1 mg/mL to 5 mg/mL (see, e.g., US’039 at col. 28 at line 62 to col. 29 at line 55). Accordingly, the prior art teaches the typical concentration range in which m-cresol is utilized in peptide-containing pharmaceutical formulations.
M-cresol was already specifically taught and known in the art for use in GLP-2 pharmaceutical formulations: Specifically, the US’039 teaches and discloses that GLP-2 compounds, formulations, and uses thereof (see, e.g., US’039 at title, abs, claims), and explicitly teaches that m-cresol was a well-known preservative known in the GLP-2 pharmaceutical arts (see, e.g., US’039 at col. 25 at lines 29-33, col. 28 at line 62 to col. 29 at line 16), was a “preferred” embodiment (see, e.g., US’039 at col. 28 at line 62 to col. 29 at line 5), and was typically utilized at ranges including 0.1 mg/mL to 5 mg/mL (see, e.g., US’039 at col. 28 at line 62 to col. 29 at line 5). Furthermore, US’039 explicitly states that “[t]he use of a preservative in pharmaceutical compositions is well-known to the skilled person” (see, e.g., US’039 at col. 29 at lines 15-21).
Accordingly, m-cresol was a well-known pharmaceutical excipient typically utilized in the GLP-2 formulation arts at the same or overlapping ranges presently claimed in order to achieve known and art-recognized benefits (see, e.g., Rowe at 203-205 and 592-594; see also US’039 at col. 28 at line 62 to col. 29 at line 55; see also MPEP § 2144.05(I), noting 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”; and further explaining that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”).
Motivation to utilize m-cresol in GLP-2 formulations: As noted above, US’039 directly pertain to GLP-2 protein formulation arts and explicitly teach, suggest, and direct artisans to utilize m-cresol (see preceding paragraph). In addition, the primary reference directly informs artisans that preservatives such as m-cresol could be utilized in the disclosed formulations (see, e.g., US’403 at col. 26 at lines 35-56), and therefore an artisan would have direct guidance to review the GLP-2 art for commonly utilized and desirable preservatives (i.e., m-cresol) taught for use in GLP-2 protein formulations, and then to add such compounds to the disclosed GLP-2 protein formulations with a reasonable expectation of successfully producing pharmaceutical formulations having the expected and predicted benefits ascribed to each substance in the prior art (e.g., m-cresol would desirably act as an antimicrobial agent against gram-positive and gram negative bacteria, yeasts, and molds, and be reasonably expected to exhibit synergistic effects with other preservatives7). Accordingly, the prior art provides guidance, motivation, and direction to utilize m-cresol in GLP-2 formulations as disclosed by the primary reference, and teaches the same or overlapping ranges as presently claimed for each component, and provides predicted and expected beneficial and desirable results attributable to the usage of such components.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
First, the invention is obvious because it is the combination of prior art elements as taught by the primary reference (e.g., the GLP-2 formulation comprising a GLP-2 analogue, L-histidine, and mannitol at a pH of 6.7 to 7.3 in aqueous solution) and the additional references (e.g., m-cresol), according to known methods of making and using GLP-2 analogue containing pharmaceutical compositions as taught by the primary reference and US’039 to yield predictable results, namely pharmaceutical compositions comprising 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, 100 mM to 230 mM mannitol, 0.1-5 mg/mL of m-cresol, and a pH of 6.7 to 7.3 in an aqueous solution, wherein such compositions would desirably have the beneficial properties ascribed to m-cresol (e.g., activities attributable to antimicrobial preservatives) (see, e.g., MPEP § 2143(I)(A), (G); see also MPEP § 2144.05(I)8). Furthermore, each component merely performs the same function in combination as it does separately.
Second, the addition of a known preservative (m-cresol) to the GLP-2 formulation disclosed by the primary reference is obvious because it amounts to the use (or application) of known techniques for improving GLP-2 formulations as taught by US’039 and the primary reference (e.g., the addition of m-cresol within known ranges), wherein the use (or application) of m-cresol within known ranges would predictably improve the base GLP-2 formulation of the primary reference in the same way, namely by augmenting the formulation to have the beneficial properties ascribed to m-cresol in the prior art (e.g., activities attributable to antimicrobial preservatives) (see, e.g., MPEP § 2143(I)(C), (D), (F), (G); see also MPEP § 2144.05(I)9). The differences between the prior art and the claimed invention were therefore encompassed in known variations of GLP-2 formulations known in the prior art.
Accordingly, the claimed invention is obvious.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to make a pharmaceutical formulation comprising prior art components having known and predictable properties, within known concentration ranges, according to known methods of forming GLP-2 pharmaceutical formulations, to obtain products exactly as taught and disclosed by the prior art. Furthermore, the prior art explicitly teaches and explains that the usage of isotonic agents and preservatives are “well-known to the skilled person”10.
No evidence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 and also commensurate in scope with the claims have been placed on record to date.
Accordingly, claims 1, 5, and 31 are rejected.
[Rejection 02]
Claims 1, 5, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 8,163,696 B2 (cited in prior action) in view of US 7,411,039 B2 (cited in previous action) and Hutchings et al.11.
Claim Interpretation: The applicable claim interpretation has been set forth above in a separate section entitled “Claim Interpretations” above, and/or discussed in preceding rejections. Those interpretations and discussions are incorporated herein unless otherwise explicitly stated. Additional claim interpretations are discussed below.
The primary reference teaches and discloses a highly similar genus of compounds. Regarding the GLP-2 analog structure recited at instant claims 1, 5, and 31, the primary reference claims methods necessitating the existence of pharmaceutical compositions comprising salts of SEQ ID NO: 34, wherein SEQ ID NO: 34 of the primary reference satisfies the GLP-2 structure of instant claim 1 wherein R1 is H, Z1 is absent, X5 is Serine, X11 is Ser, Z2 is (K)6, and R2 is NH2 (compare US’696 at claims 1-4, SEQ ID NO: 36 with instant claims 1-2 and “ZP1848”). Therefore, the specific GLP-2 analog of ZP1848 is a prior art structure. Regarding instant claims 1, 5, 31, and the concentrations of the GLP-2 analogue, L-histidine, mannitol, and the pH, the primary reference explicitly teaches, discloses, and directs artisans to utilize pharmaceutically acceptable compositions of the recited GLP-2 analog suitable for use in the recited methods (see, e.g., US’696 at claims 1-4); and specifically directs artisans to utilize pharmaceutical formulations comprising 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 100 mM to 230 mM, pH of 6.7 to 7.3 in an aqueous solution (see, e.g., US’696 at col 30 at lines 10-30) (see also MPEP § 2144.05(I), noting 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”). Regarding claims 1, 5, 31, and the presence of m-cresol, the primary reference explicitly teaches and discloses that the GLP-2 analogue formulations may comprise preservatives, and explicitly directs artisans to utilize m-cresol (see, e.g., US’696 at col. 28 at lines 20-35, col. 27 at lines 35-55).
The disclosure of the primary reference differs from the instant claims as follows: although the primary reference discloses that the disclosed formulations may comprise m-cresol, the primary reference does not explicitly teach or disclose the usage of 3.15 mg/ml of meta-cresol as required by amended claim 1.
Regarding claims 1, 5, 31, and m-cresol: M-cresol was a prior art element, namely a well-known pharmaceutical excipient taught for use in the GLP-2 pharmaceutical arts (see, e.g., US’039 at title, abs, col. 28 at line 62 to col. 29 at line 55, claims). More specifically, US’039 teaches and discloses that m-cresol was a well-known preservative known in the GLP-2 pharmaceutical arts (see, e.g., US’039 at col. 25 at lines 29-33, col. 28 at line 62 to col. 29 at line 16), was a “preferred” embodiment (see, e.g., US’039 at col. 28 at line 62 to col. 29 at line 5), and was typically utilized at ranges including 0.1 mg/mL to 5 mg/mL (see, e.g., US’039 at col. 28 at line 62 to col. 29 at line 5), wherein US’039 explicitly states that “[t]he use of a preservative in pharmaceutical compositions is well-known to the skilled person” (see, e.g., US’039 at col. 29 at lines 15-21). US’039 exemplifies the usage of 3 mg/mL of m-cresol in multiple formulations (see, e.g., US’039 at col. 38 at lines 50-64). Accordingly, an artisan in the GLP-2 analogue and protein formulation arts would readily appreciate that m-cresol could be utilized in GLP-2 analogue formulations at 0.1 mg/mL to 5 mg/mL and would be directed to 3 mg/mL (see, e.g., MPEP § 2144.05(I), noting 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”; and further explaining that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”).
Art-recognized problem regarding antimicrobial preservatives and art-recognized solutions: Although the prior art teaches that GLP-2 analogue formulations may comprises m-cresol (see, e.g., US’696 at col. 28 at lines 20-35, col. 27 at lines 35-55) at 0.1 mg/mL to 5 mg/mL (see, e.g., US’039 at col. 28 at line 62 to col. 29 at line 5), it was known in the art that m-cresol could cause protein aggregation. More specifically, Hutchings identifies an art-recognized problem, namely that multi-dose protein formulations require antimicrobial preservatives to extend shelf-life, but antimicrobial preservatives are also known to cause protein aggregation (see, e.g., Hutchings at title, abs, 374-375 at bridging ¶; see also Hutchings at title, abs, 365-366 at bridging ¶, 366 at Table 1, 366 at col I at 1st full ¶, noting that m-cresol is one of only five commonly utilized antimicrobial preservatives in liquid protein formulations, including m-cresol). Accordingly, although an artisan in the GLP-2 analogue formulation arts would add m-cresol at 0.1 to 5 mg/mL in formulations to desirably acts as an antimicrobial preservative and predictably extend shelf-life, an artisan would also appreciate that m-cresol would predictably cause protein aggregation. Therefore, protein aggregation upon addition of m-cresol is not a surprising outcome, but is instead a known and expected issue in liquid protein formulations. Notably, solutions for protein aggregation were already known in the GLP-2 arts.
Art-recognized solution addressing protein aggregation: US’403 explicitly identifies that the disclosed GLP-2 analogue formulations may comprise m-cresol (see, e.g., US’696 at col. 28 at lines 20-35, col. 27 at lines 35-55), and explicitly informs artisans that protein aggregation may be prevented by the addition of organic solubilizers, such as “acetic acid or acetate and salts thereof” (see, e.g., US’696 at col. 27 at lines 46-54). This is pertinent because acetate is a pharmaceutically acceptable salt usable for GLP-2 analogues (see, e.g., US’696 at col. 26 at lines 29-38) and acetic acid may be utilized to adjust pH to a desired level, and US’403 explicitly teaches and directs artisans to utilize acetic acid is explicitly exemplified as an optional component that may be present “up to 200 mM” in the exemplified formulas (see, e.g., US’696 at col 29 at lines 1 to col. 30 at line 30), wherein the pH range could be varied from 6.5 to 7.5 and preferably 6.7 to 7.3 (see id.). Accordingly, an artisan adding m-cresol to a GLP-2 analogue formulation to desirably improve shelf-life would readily appreciate that acetic acid could be added to address protein aggregation within the acceptable concentration and pH ranges taught and disclosed by the prior art, and would readily appreciate that adding acetic acid would lower the pH of the formulation. Regarding instant claims 1, 5, 31, 3.15 mg of m-cresol, and a pH of between 6.0 and 6.8, the prior art directs artisans to utilize pharmaceutical formulations comprising 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 100 mM to 230 mM, acetic acid up to 200 mM, and a pH of 6.7 to 7.312 in an aqueous solution (see, e.g., US’696 at col 30 at lines 10-30)13, wherein such formulations may also comprise m-cresol (see, e.g., US’696 at col. 28 at lines 20-35, col. 27 at lines 35-55), which would be added at 0.1 mg/mL to 5 mg/mL (see, e.g., US’039 at col. 28 at line 62 to col. 29 at line 5) 14. As noted above, if protein aggregation was observed upon addition of m-cresol, an artisan would solve this issue by adding acetic acid “up to 200 mM” (see, e.g., US’696 at col. 27 at lines 46-54, col 30 at lines 10-30), which would necessarily lower the pH. Accordingly, an artisan would readily appreciate that the amount of m-cresol utilized would be directly correlated to (i) the level of antimicrobial preservative functionality achieved and (ii) the amount of acetic acid that would need to be added to counteract any unwanted protein aggregation caused by added m-cresol, wherein added acetic acid would lower the pH. Per MPEP § 2144.05(I) 15, all claimed ranges clearly overlap with the ranges of each component already taught and disclosed in the prior art. Furthermore, per MPEP § 2144.05(II), it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable because "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation" (see, e.g., Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955)), and "No invention is involved in discovering optimum ranges of a process by routine experimentation" (see, e.g., Id. at 458, 105 USPQ at 236-237), since the "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art" (see, e.g., Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Here, the amount of acetic acid and m-cresol utilized are correlated and result-effect variables as explained above, wherein addition of acetic acid to counteract protein aggregation caused by m-cresol would lower the pH, and wherein such GLP-2 formulations would predictably and expectedly yield desirably formulations so long as each component and parameter remains within the permissible ranges taught by the prior art. Accordingly, because Applicant has not disclosed that the specific limitations recited in instant claims 1, 5, and 31 are for any particular purpose or solve any stated problem that was not already known in the prior art, and no teachings of criticality of range commensurate in scope with the requirements of MPEP § 2144.05(III)(A), § 716, § 716.01, and § 716.02 have been placed on record to date, and the prior art teaches that the concentrations of each component concentration (and the pH) may vary within a known range (see, e.g., US’696 at col. 28 at lines 20-35, col. 27 at lines 35-55, col 30 at lines 10-30; see, e.g., US’039 at col. 28 at line 62 to col. 29 at line 5)16, and the prior art teaches that such ranges would desirably lead to a GLP-2 analogue formulation, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the GLP-2 analogue formulation arts.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The invention is obvious because it is the combination of prior art elements as taught by the primary reference (e.g., the GLP-2 formulation comprising a GLP-2 analogue, L-histidine, acetic acid, and mannitol at a pH of 6.7 to 7.3 in aqueous solution) and the additional references (e.g., m-cresol), according to known methods of making and using GLP-2 analogue containing pharmaceutical compositions as taught by the primary reference and US’039, in order to predictably yield pharmaceutical formulations comprising 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, 100 mM to 230 mM mannitol, 0.1-5 mg/mL of m-cresol, up to 200 mM of acetic acid, and having a pH of pH of 6.7 to 7.3 in an aqueous solution, wherein such compositions would desirably have improved shelf-life attributable to m-cresol as disclosed by Hutchings, and wherein acetic acid would be added to address any protein aggregation caused by m-cresol (see, e.g., MPEP § 2143(I)(A), (G); see also MPEP § 2144.05(II) and (I)17). Furthermore, each component merely performs the same function in combination as it does separately.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to make a pharmaceutical formulation comprising prior art components having known and predictable properties, within known concentration ranges, according to known methods of forming GLP-2 pharmaceutical formulations, to obtain products exactly as taught and disclosed by the prior art. Furthermore, addressing known issues regarding known components (e.g., protein aggregation caused by m-cresol) using known solutions (e.g., addition of acetic acid, which would lower pH) to achieve predicted and expected solutions (e.g., a pharmaceutical formulations desirably comprising an antimicrobial functionality, and having an extended shelf-life, but without protein aggregation) is well within the ordinary skill in the art, because such additives are “well-known to the skilled person”18.
No evidence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 and also commensurate in scope with the claims have been placed on record to date.
Accordingly, claims 1, 5, and 31 are rejected.
Response to Arguments
Applicant's arguments filed 2/23/2026 have been fully considered but they are not persuasive. In view of the revised rejections based upon references and rationales previously set forth on record, Examiner’s prior response of record remains applicable and is incorporated into the instant response. Applicable arguments pertaining to the revised rejections are addressed below.
Amendments filed 2/23/2026: It is the Examiner’s understanding that Applicant identifies that the claim scope has been amended to require “consisting of” language, exclude polypropylene glycol, and to require m-cresol to be present at 3.15 mg/mL (see, e.g., Reply filed 2/23/2026 at 4 at 2nd ¶, 5 at 1st full ¶, 6 at 2nd ¶). Examiner notes that the claim recites “comprising” language as well, which has necessitated a rejection under 35 USC 112(b). In addition, Examiner notes that the prior art teaches all claimed components, including m-cresol, at ranges that overlap the recited values, wherein the expected and predicted function of each component is explicitly identified in the prior art.
Prima facie obviousness has been established: As an initial matter, it is the Examiner’s understanding that Applicant fails to dispute the Examiner’s explicitly recited rationales supporting a determination of obviousness as set forth on record (i.e., MPEP § 2143(I)(A), (C), (D), (F), (G), and MPEP §§ 2144.05(I)-(II)). In the absence of arguments addressing the merits of such rationales, such arguments are understood to be undisputed on record.
Multiple holdings are understood to be undisputed on record: It is the Examiner’s understanding that Applicant does not dispute that all components recited in the pending claims (e.g., ZP1848-acetate, meta-cresol, histidine buffer, mannitol, pH, acetic acid) are prior art elements. It is the Examiner’s understanding that Applicant does not dispute that the prior art of record establish that the typical concentration ranges utilized for each prior art component overlap or lie within the explicit ranges taught and suggested by the prior art.
All rejections have been addressed collectively: It is the Examiner’s understanding that Applicant has addressed all rejections under 35 USC 103 collectively (see, e.g., Reply filed 2/23/2026 at 4 at § “Rejections Under 35 U.S.C. § 103” to page 7 at 1st full ¶), and therefore the arguments are addressed collectively. Applicant has previously referred, collectively, to all primary references in each rejection as “The Larsen Patents” (see, e.g., Reply filed 1/23/2025 at 6-7 at bridging ¶). Examiner notes that the record has been simplified by withdrawing cumulative rejections supporting a determination of obviousness based upon the same rationales.
Applicant summarizes and addresses a portion of the Examiner’s prior response to arguments: It is the Examiner’s understanding that Applicant provides a summary of a portion of the Examiner’s prior response (see, e.g., Reply filed 2/23/2026 at 4-5 at bridging ¶ showing bulleted list). Specifically, Applicant appears to reiterate the Examiner’s position regarding allegations of unexpected results (see id), and then provides statements attempting to rebut the Examiner’s position (see, e.g., Reply filed 2/23/2026 at 5 at 2nd full ¶ to page 7 at 1st partial ¶). Therefore, it is the Examiner’s understanding that Applicant fails to rebut the determinations and rationales supporting a determination of obviousness under MPEP § 2143(I)(A), (C), (D), (F), (G), and MPEP § 2144.05(I)-(II) of record, but instead attempts to rebut the prior rejections by again alleging unexpected results. These arguments are addressed below.
Examiner may rely upon a rationale that differs from the Applicant’s rationale: It is the Examiner’s understanding that Applicant identifies that their rationale for arriving at the claimed invention differs from the rationale relied upon by the Examiner to establish obviousness (see, e.g., Reply filed 2/23/2026 at 5 at 2nd full ¶, alleging that lowering pH stabilizes formulations with m-cresol). Examiner notes that these arguments not persuasive because an examiner may support a determination of obviousness by relying upon a rationale that differs from the Applicant’s rationale (see, e.g., MPEP § 2144(IV)). Here, the Examiner’s rationales are explicitly identified in the rejection (i.e., MPEP § 2143(I)(A), (C), (D), (F), (G), and MPEP § 2144.05(I)), but Applicant fails to address or specifically dispute these rationales supporting a determination of obviousness.
Allegations suggesting “lack of predictability” or “lack of reasonable expectation of success”: It is the Examiner’s understanding that Applicant is alleging a lack of predictability or otherwise a lack of reasonable expectation of success (see, e.g., Reply filed 2/23/2026 at 4 at § “Rejections Under 35 U.S.C. § 103” to page 7 at 1st full ¶). This is not persuasive because the Applicant’s assertions do not reflect the proper legal standards for evaluating predictability. MPEP § 2143.02(II) explains that “[o]bviousness does not require absolute predictability”, but instead clarifies that only “at least some degree of predictability is required” (see, e.g., MPEP § 2143.02(II)). Here, the rejection explicitly addresses predictability and reasonable expectation of success, but Applicant fails to address the explicitly identified predicted and expected results set forth in the rejection. Here, the Examiner’s basis for “predictability” is merely based upon the presumption that the prior art is fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). As explained at MPEP § 2143.02, predictability and reasonable expectation of success are satisfied when “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 would have yielded nothing more than predictable results to one of ordinary skill in the art”. Here zero evidence of unexpected results commensurate in scope with the requirements of MPEP 716.02 have been set forth on record, all elements of the claimed invention were known in the prior art, one of ordinary skill was fully enabled to combined each component using routine methods in the biochemical arts per the guidance of the primary reference, and the elements would have merely performed their art-recognized, respective functions (see Rejection, above). Accordingly, such arguments are not persuasive.
Allegations of unexpected results: It is the Examiner’s understanding that Applicant repeatedly alleges the existence of unexpected results commensurate in scope with the requirements of MPEP §716, §716.01, and §716.02, wherein such results are sufficient to rebut prima facie obviousness (see, e.g., Reply filed 2/23/2026 at 4-5 at bulleted list, 5 at 2nd and final full ¶¶, 6 at 1st ¶ to 6 at final ¶, 7 at 1st partial ¶). However, to establish such unexpected results, the allegations must be timely and supported by objective evidence (see, e.g., 37 C.F.R. 1.132; see MPEP §§ 716.01, 716.01(a), 716.01(c)); to be of probative value the proffered evidence must be related to the claimed invention (see MPEP §§ 716.01(b), discussing nexus requirement and noting that "[w]here the offered secondary consideration actually results from something other than what is both claimed and novel in the claim, there is no nexus to the merits of the claimed invention"); the evidence must establish that the expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), which is fully explained (see, e.g., MPEP § 716.02(b)(II)), commensurate in scope with the claimed invention (see, e.g., MPEP § 716.02(d)), and wherein a comparison of the claimed invention with the closest prior art of record is provided (see, e.g., MPEP § 716.02(e)). Furthermore, even if evidence satisfying MPEP §§ 716.02, 716.02(a), 716.02(b), 716.02(d), and 716.02(e) is set forth on record, such evidence may not be sufficient to rebut prima facie obviousness because the evidence of expected and unexpected results must be weighed (see, e.g., MPEP § 716.02(c)(I)) and the totality of the record considered (see, e.g., MPEP §§ 716.01(d), 716.02(f)), including teachings in the prior art and evidence of expected results which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)). In the instant case, the proffered data does not satisfy the requirements of MPEP § 716.02 as follows:
First, the proffered data show no variation in the amount of ZP1848 utilized, the amount of Histidine utilized, and no variation in the pharmaceutical salt of ZP1848 utilized (see, e.g., Spec. filed 3/25/2021 at Table 1 and 2). Therefore. even assuming arguendo that unexpected results exist, such results have not been shown to exist commensurate in scope with the pending claims (see, e.g., MPEP § 716.02(d)(I)), and no evidence of criticality of range has been established (see, e.g., MPEP § 716.02(d)(II)). In addition, Formulation 7 at Table 2 shows that pH values taught by the prior art under the claimed minimum of 6.0 still exhibit no precipitation, which suggests that the claimed pH range does not correspond to a critical range.
Second, the relevance and statistical significance of the proffered data is unclear and not explained as required to satisfy the Applicant’s burden (see, e.g., MPEP §§ 716.01, 716.02(b)(I)-(II)). This is because Tables 1-2 lack any indication of statistical significance or explanation of how the “visual appearance” was meaningfully measured (i.e., it is unclear if absorbance was measured using spectroscopy or simply opined by eyesight only). Presumably, the reported data is a qualitative observation regarding a visual appearance, rather than a quantitative analysis by chromatography, turbidity measurements, activity measurements, etc. Accordingly, the relevance of the proffered data is not fully explained (see, e.g., MPEP §§ 716.01, 716.02(b)(II)), and no statistical analysis evidencing the existence of unexpected and unobvious results of both statistical and practical significance has been placed on record that satisfies Applicant’s burden (see, e.g., MPEP § 716.02(b)(I)).
Third, per MPEP § 716.02(c), “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness”. This is pertinent because the prior art of Hutchings explains that m-cresol would be expected and predicted to cause protein aggregation (see, e.g., Rejections, above; see also Hutchings at title, abs, 365-366 at bridging ¶, 366 at Table 1, 366 at col I at 1st full ¶, 374-375 at bridging ¶), which was an art-recognized problem since Hutchings explains that multi-dose protein formulations require antimicrobial preservatives to extend shelf-life, but antimicrobial preservatives are also known to cause protein aggregation (see, e.g., Hutchings at title, abs, 374-375 at bridging ¶; see also Hutchings at title, abs, 365-366 at bridging ¶, 366 at Table 1, 366 at col I at 1st full ¶, noting that m-cresol is one of only five commonly utilized antimicrobial preservatives in liquid protein formulations, including m-cresol). This is pertinent because visual protein aggregates caused by m-cresol would be expected. Furthermore, the art-recognized solution for reducing protein aggregation was to add acetic acid (see, e.g., US’696 at col. 27 at lines 46-54), which would predictably lower pH values. Accordingly, an increased shelf-life and both a reduction of pH and a reduction of protein aggregation upon addition of both acetic acid and m-cresol is the expected result. Accordingly, data showing expected results weigh in favor of a determination of obviousness, not non-obviousness per MPEP § 716.02(c)(II).
Accordingly, in view of the totality of evidence of record and the express teachings of the prior art, the evidence weighs in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(I)) because the proffered data shows expected results, and the formulations fall within the scope of the ranges of concentrations and pH values taught and disclosed by the prior art of record.
Using a pH range that substantially overlaps with the prior art pH ranges does not weigh in favor of non-obviousness: It is the Examiner’s understanding that Applicant is alleging that using the use of pH values of 6.0 to 6.8 led to increased stability relative to the closest prior art per MPEP § 716.02(e)(I)-(III) (see, e.g., Reply filed 2/23/2026 at 4-5 at bulleted list, 5 at 2nd and final full ¶¶, 6 at 1st ¶ to 6 at final ¶, 7 at 1st partial ¶; see also Reply filed 9/11/2025 at 5 at final ¶ to 6 at final ¶). This is not persuasive because the prior art of record explicitly taught ZP1848 formulations having pH values ranging below 7.0, including a pH of 6.7 (see rejections, maintained above). Accordingly, the use of a pH value within the typical range known and taught in the prior art is prima facie obvious (see, e.g., MPEP § 2144.05(I)19). The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Furthermore, as explained above, m-cresol was known in the prior art to cause protein aggregation, and an artisan would have known to add acetic acid (thereby lowering pH) to address protein aggregation, exactly as taught by the prior art of record. Accordingly, no evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record at this time.
Examiner did not rely upon improper hindsight reasoning: It is the Examiner’s understanding that Applicant is alleging that the claimed combination is not obvious prior to the disclosure of the instant Application (see Reply filed 9/11/2025 at 7 at 1st ¶) at final sentence. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant fails to identify any teachings or disclosures from the instant Application relied upon by the Examiner. Rather, the Examiner’s rationale for combining the claimed components of the originally elected species differ from the Applicant’s rationale (see, e.g., MPEP § 2144(IV)). Here, the Examiner’s rationales are explicitly identified in the rejection (i.e., MPEP § 2143(I)(A), (C), (D), (F), (G), and MPEP § 2144.05(I)), but Applicant fails to address or specifically dispute these rationales supporting a determination of obviousness.
In summary, all arguments and evidence proffered by Applicant have been fully considered but not found persuasive for the reasons discussed above. Accordingly, the claims are prima facie obviousness under multiple rationales (i.e., MPEP § 2143(I)(A), (C), (D), (F), (G), and MPEP § 2144.05(I)-(II)). The arguments do not establish the existence of any unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02, but appear to show only the expected and predicted results, which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)). Therefore, the arguments fail to materially distinguish the invention, as claimed, from the prior art cited in the rejections.
Accordingly, the claims remain rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20070231308A1 (cited in previous action) pertains to related GLP-2 sequences (see, e.g., id. at title, abs, claims).
US20170137487A1 (cited in previous action) pertains to related GLP-2 sequences, and corresponds to abandoned Application 15/411,649.
WO2006/117565A1 (Nov. 9, 2006; Larsen et al., cited in previous action) provides a disclosure similar to US 7,745,403 B2 (Jun. 29, 2010). WO’564 teaches and discloses at least compound 1848, which has the following structure:
HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK-NH2,
and is identified as [Gly2, Glu3, Thr5, Ser8, Leu10, Ala 11, 16, 24, 28]hGLP-2(1-33)-(Lys)6-NH2 (see, e.g., WO’565 at 20 at lines 39-40, 22 at lines 4-12, 42 at “1848”, claim 11, 14, passim). WO’565 explicitly teaches and directs artisans to GLP-2 analogue formulations comprising “most preferably from 10 to 30 mg/mL” of a therapeutic GLP-2 analogue (see, e.g., WO’565 at 32 at line 15 to page 33 at line 6). WO’565 explicitly teaches and directs artisans to GLP-2 analogue formulations comprising “most preferably from 5 to 50 mM L-histidine” (see, e.g., WO’565 at 32 at line 15 to page 33 at line 6; see esp. id. at 32 at line 34). WO’565 explicitly teaches and directs artisans to GLP-2 analogue formulations comprising “most preferably from 100 mM to 230 mM” of mannitol (see, e.g., WO’565 at 32 at line 15 to page 33 at line 6).
US 7,563,770 B2 (Jul. 21, 2009; cited in previous action) provides a disclosure similar to US 7,745,403 B2 (Jun. 29, 2010; cited in previous action). US’770 claims pharmaceutical salts of SEQ ID NO: 34, which satisfies instant claim 1 wherein R1 is H, Z1 is absent, X5 is Serine, X11 is Ser, Z2 is (K)6, and R2 is NH2 (see, e.g. US’770 at claims 1-2, SEQ ID NO: 34). US’770 identifies that expressly disclosed pharmaceutical formulations comprised 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 100 mM to 230 mM, arginine up to 200 mM with a pH of 6.7 to 7.3, and acetic acid at 0.5 to 50 mM in an aqueous solution, wherein the acetic acid would necessarily form an acetate salt of the GLP-2 analogue (see, e.g., US’770 at col 29 at lines 3-23).
U.S. Patent No. 8,263,552 B2 (cited in prior action) claims methods necessitating the existence of pharmaceutical compositions comprising salts of SEQ ID NO: 34, wherein SEQ ID NO: 34 of the primary reference satisfies the GLP-2 structure of instant claim 1 wherein R1 is H, Z1 is absent, X5 is Serine, X11 is Ser, Z2 is (K)6, and R2 is NH2 (compare US’552 at claims 1-8, SEQ ID NO: 36 with instant claims 1-2 and “ZP1848”). Therefore, the specific GLP-2 analog of ZP1848 is a prior art structure. The primary reference explicitly teaches, discloses, and directs artisans to utilize pharmaceutically acceptable compositions of the recited GLP-2 analog suitable for use in the recited methods (see, e.g., US’552 at col 30 at lines 7 to 30); and specifically directs artisans to utilize pharmaceutical formulations comprising 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 100 mM to 230 mM, pH of 6.7 to 7.3 in an aqueous solution (see, e.g., US’552 at col 30 at lines 7 to 30).
U.S. Patent No. 9,125,882 B2 (cited in prior action) claims methods necessitating the existence of pharmaceutical compositions comprising salts of SEQ ID NO: 34, wherein SEQ ID NO: 34 of the primary reference satisfies the GLP-2 structure of instant claim 1 wherein R1 is H, Z1 is absent, X5 is Serine, X11 is Ser, Z2 is (K)6, and R2 is NH2 (see, e.g., US’882 at claims 1-11, passim; compare US’882 at claims 1, 3, and 5-7, SEQ ID NO: 36 with instant claims 1-2 and “ZP1848”). Therefore, the specific GLP-2 analog of ZP1848 is a prior art structure. The primary reference explicitly teaches, discloses, and directs artisans to utilize pharmaceutically acceptable compositions of the recited GLP-2 analog suitable for use in the recited methods (see, e.g., US’882 at col 32 at lines 10-35, at claims 1, 3, 5-7).; and specifically directs artisans to utilize pharmaceutical formulations comprising 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 100 mM to 230 mM, pH of 6.7 to 7.3 in an aqueous solution (see, e.g., US’882 at col 32 at lines 10-35, at claims 1, 3, 5-7).
U.S. Patent No. 9,580,487 B2 (cited in prior action) claims methods necessitating the existence of pharmaceutical compositions comprising salts of SEQ ID NO: 34, wherein SEQ ID NO: 34 of the primary reference satisfies the GLP-2 structure of instant claim 1 wherein R1 is H, Z1 is absent, X5 is Serine, X11 is Ser, Z2 is (K)6, and R2 is NH2 (see, e.g., US’487 at claims 1-20, passim; compare US’487 at claims 1-20, SEQ ID NO: 36 with instant claims 1-2 and “ZP1848”). Therefore, the specific GLP-2 analog of ZP1848 is a prior art structure. The primary reference explicitly teaches, discloses, and directs artisans to utilize pharmaceutically acceptable compositions of the recited GLP-2 analog suitable for use in the recited methods (see, e.g., US’487 at col 32 at lines 45-65, at claims 1-20); and specifically directs artisans to utilize pharmaceutical formulations comprising 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 100 mM to 230 mM, pH of 6.7 to 7.3 in an aqueous solution (see, e.g., US’487 at col 32 at lines 45-65, at claims 1-20)
WO2005/049061 A2 (cited in previous action) discloses that M-cresol was a well-known pharmaceutical excipient (see, e.g., WO’06120 at 13 at line 34 to page 14 at line 12, p. 20 at lines 17-25). WO’061 teaches that peptide pharmaceutical formulations may comprise a preservative such as m-cresol at a preferable range of “about 1 mg/ml to about 10 mg/ml” (see, e.g., WO’061 at 13 at line 34 to page 14 at line 12); Accordingly, m-cresol was a well-known pharmaceutical excipient typically utilized in the GLP-2 formulation arts at the same or overlapping ranges presently claimed in order to achieve known and art-recognized benefits (see, e.g., WO’06121 at 13 at line 34 to page 14 at line 12, p. 20 at lines 17-25).
Zapadka et al.22 addresses factors impacting the physical stability (aggregation) of peptide therapeutics (see, e.g., id. at title, abs), which includes peptide concentration and pH (see, e.g., id. at abs, 4 at §§ 2.1 to 7 at §§ 2.3 “pH and net charge”), as well as preservatives such as m-cresol (see, e.g., id. at 10 at col II at § 2.7.7).
Conclusion
No claims are allowed.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 Wherein [x](mM) = C(mg/mL) / MW(g/mol) *1000.
2 Rowe et al., Handbook of Pharmaceutical Excipients, 6th Ed., 917 pages, Published by Pharmaceutical Press 2009, excerpt of title, table of contents at i-ix, and pages 203-205 and 592-594; hereafter “Rowe”; cited in previous action.
3 Rowe et al., Handbook of Pharmaceutical Excipients, 6th Ed., 917 pages, Published by Pharmaceutical Press 2009, excerpt of title, table of contents at i-ix, and pages 203-205 and 592-594; hereafter “Rowe”; cited in previous action.
4 Rowe et al., Handbook of Pharmaceutical Excipients, 6th Ed., 917 pages, Published by Pharmaceutical Press 2009, excerpt of title, table of contents at i-ix, and pages 203-205 and 592-594; hereafter “Rowe”; cited in previous action.
5 Rowe et al., Handbook of Pharmaceutical Excipients, 6th Ed., 917 pages, Published by Pharmaceutical Press 2009, excerpt of title, table of contents at i-ix, and pages 203-205 and 592-594; hereafter “Rowe”; cited in previous action.
6 Rowe et al., Handbook of Pharmaceutical Excipients, 6th Ed., 917 pages, Published by Pharmaceutical Press 2009, excerpt of title, table of contents at i-ix, and pages 203-205 and 592-594; hereafter “Rowe”; cited in previous action.
7 See, e.g., Rowe at 203 at §6, 204 at §10, 205 at §18.
8 See MPEP § 2144.05(I), noting 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”; and further explaining that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”).
9 See MPEP § 2144.05(I), noting 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”; and further explaining that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”). Here, all claimed ranges lie inside prior art range or otherwise are “merely close” to “about 100 mg/mL” of propylene glycol.
10 See, e.g., US’039 at col. 29 at lines 15-21 and 50-55.
11 Hutchings et al., Effect of antimicrobial preservatives on partial protein unfolding and aggregation. J Pharm Sci. 2013 Feb;102(2):365-76. doi: 10.1002/jps.23362. Epub 2012 Nov 20. PMID: 23169345; PMCID: PMC3990441; hereafter “Hutchings”.
12 A pH of 6.7 to 7.3 is a “most preferable” range, but the disclosure broadly identifies that the pH may range from 4 to 8, or 6.5 to 7.5. Notably, these ranges overlap in scope with the instantly claimed pH ranges. see also MPEP § 2144.05(I), noting 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”.
13 see also MPEP § 2144.05(I), noting 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”
14 see also MPEP § 2144.05(I), noting 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”
15 see also MPEP § 2144.05(I), noting 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”
16 see also MPEP § 2144.05(I), noting 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”
17 See MPEP § 2144.05(I), noting 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”; and further explaining that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”). Here, all claimed ranges lie inside prior art range or otherwise are “merely close” to “about 100 mg/mL” of propylene glycol.
18 See, e.g., US’039 at col. 29 at lines 15-21 and 50-55.
19 See MPEP § 2144.05(I), noting 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”; and further explaining that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”). Here, all claimed ranges lie inside prior art range or otherwise are “merely close” to “about 100 mg/mL” of propylene glycol.
20 The disclosure of WO’061 is understood to be applicable to GLP-2 protein formulations (see, e.g., WO’061 at p. 4 at line 26 to p. 5 at line 26, p. 12 at lines 25-26).
21 The disclosure of WO’061 is understood to be applicable to GLP-2 protein formulations (see, e.g., WO’061 at p. 4 at line 26 to p. 5 at line 26, p. 12 at lines 25-26).
22 Zapadka et al., Factors affecting the physical stability (aggregation) of peptide therapeutics. Interface Focus. 2017 Dec 6;7(6):20170030. doi: 10.1098/rsfs.2017.0030. Epub 2017 Oct 20. PMID: 29147559; PMCID: PMC5665799; hereafter “Zapadka”.