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 .
Claim Status
Claims 1, 31, 36-41, and 46 are pending. Claim 5 was canceled, and claim 1 was amended in the Reply filed 7/24/2026. Claims 36-41 and 46 remain withdrawn as directed to a non-elected invention. Claims 1 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 originally 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); wherein 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 was then extended to the 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; which was previously deemed obvious for reasons of record (see, e.g., Action mailed 3/26/2026 at 10-23).
In the response filed 7/24/2026, the claims were amended to exclude the non-elected species. Per MPEP § 803.02(III)(A), examination was then extended to the non-elected species of formulation comprising 10 mg/mL ZP1848, a pH of 6.0 and 6.8, 230 mM mannitol, 15 mM histidine buffer, 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Claims 36-41 and 46 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Claims 1 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 7/24/2026 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 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.
Claim 1 was amended in the Reply filed 7/24/2026 to include a “wherein” clause, namely “wherein the formulation is physically stable for 26 weeks at °C”. Per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”. Here, the “wherein” clause does not unambiguously correspond to a clear structure/function relationship in the original disclosure, and therefore is not reasonably interpreted as a functional limitation; this determination is further supported by the observation that amended claim 1 “consists of” specifically enumerated components present at specific concentrations and at a specific pH range, wherein very little variability is permitted by the claim scope (e.g., pH may range, the “histidine buffer” may have minor non-histidine components, and the pharmaceutical salt may vary). Accordingly, the “wherein” clause is understood to merely recite an intended or expected result fully satisfied by the positively recited steps and/or structures set forth in the body of amended claim 1. Therefore, the “wherein” clause of “wherein the formulation is physically stable for 26 weeks at °C” is understood to be fully satisfied by all prior art embodiments that consist of 10 mg/mL of ZP1848, 3.15 mg/mL meta-cresol, 15 mM histidine buffer, 230 mM mannitol, and a pH of 6.0-6.8 optionally adjusted using acetic acid and/or L-arginine.
Additional claim interpretations are provided below.
Withdrawn Claim Rejections
The rejection of claims 1, 5, and 31 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the cancellation of claim 5 and amendments to claim 1, as filed 7/24/2026.
The rejection of claim 5 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn as moot in view of the cancellation of claim 5.
The rejection of 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.2 and US 7,411,039 B2 (cited in previous action) is withdrawn in view of the cancellation of claim 5 and amendments to claim 1. A new or revised rejection is set forth below, as necessitated by Applicant amendment.
The rejection of 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.3 is withdrawn in view of the cancellation of claim 5 and amendments to claim 1. A new or revised rejection is set forth below, as necessitated by Applicant amendment.
Claim Objections
Amended claim 1 is objected to because of the following informalities: The amended phrase “A aqueous pharmaceutical….” should be “An aqueous pharmaceutical….” at line 1 of claim 1.
Appropriate correction is required.
New or Revised Claim Rejections as Necessitated by Applicant Amendment
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 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.4 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, 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 1-100 and most preferably 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 100 mM to 230 mM, a pH of 6.5 to 7.5 and most preferably from 6.7 to 7.3 in an aqueous solution, that may be optionally adjusted with L-arginine and/or acetic acid (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”).
The disclosure of the primary reference differs from the instant claims as follows: although the primary reference directs artisans to make and use GLP-2 aqueous formulations comprising the same or overlapping amounts of identical components at the same or overlapping pH range, the primary reference does not explicitly teach or disclose formulations comprising 3.15 mg/ml of meta-cresol as required by amended claim 1.
However, regarding claims 1, 31, and the presence of m-cresol, the primary reference does explicitly teach, disclose, and direct artisans to add preservatives to such GLP-2 analogue formulations, and specifically identifies that such formulations may include the preservative of m-cresol (see, e.g., US’403 at col. 26 at lines 25-56, col. 25 at lines 35-55). Therefore, the primary difference between the primary reference and amended claim scope is the amount of m-cresol being utilized.
Regarding claims 1, 31, and m-cresol: in view of the guidance of the primary reference, and artisan would review the prior art, and would readily appreciate that 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 preservatives5). 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)6). 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)7). 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”8.
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 and 31 are rejected.
[Rejection 02]
Claims 1 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.9.
Claim Interpretation: The applicable claim interpretation has been set forth above in a separate section entitled “Claim Interpretations” above, and/or discussed in a preceding rejections. Those interpretations and discussions are incorporated herein unless otherwise explicitly stated. Additional claim interpretations are discussed below.
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’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, 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 1-100 mg/mL and most preferably 10-30 mg/mL of GLP-2 analogue, 5 to 50 mM L-histidine, Mannitol at 30-300 mM and most preferably 100 mM to 230 mM, a pH of 6.5 to 7.5 and most preferably a pH of 6.7 to 7.3 in an aqueous solution, wherein L-arginine and acetic acid may be optionally present (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”).
The disclosure of the primary reference differs from the instant claims as follows: although the primary reference directs artisans to make and use GLP-2 aqueous formulations comprising the same or overlapping amounts of identical components at the same or overlapping pH range, the primary reference does not explicitly teach or disclose formulations comprising 3.15 mg/ml of meta-cresol as required by amended claim 1.
However, regarding claims 1, 31, and the presence of m-cresol, the primary reference does explicitly teach, disclose, and direct artisans to add preservatives to such GLP-2 analogue formulations, and specifically identifies that such formulations may include the preservative of m-cresol (see, e.g., US’696 at col. 28 at lines 20-35, col. 27 at lines 35-55). Therefore, the primary difference between the primary reference and amended claim scope is the amount of m-cresol being utilized.
Regarding claims 1, 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, 31, and 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 7.310 in an aqueous solution (see, e.g., US’696 at col 30 at lines 10-30)11, 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) 12. 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) 13, 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)14, 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)15). 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”16.
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 and 31 are rejected.
Response to Arguments
Applicant's arguments filed 7/24/2026 have been fully considered but they are not persuasive for the reasons set forth below.
As an initial matter, in view of the revised rejections based upon references and rationales previously set forth on record, Examiner’s prior response of record remains pertinent.
Allegations of “heretofore unknown precipitation” is not persuasive: Applicant alleges that “lowering the pH to between 6.0 and 6.8 in the claimed formulations corrects the undesirable and heretofore unknown precipitation caused by adding the preservative m-cresol at 3.15 mg/mL in ZP1848 formulations at pH 7.0” (see, e.g., Reply filed 7/24/2026 at 5 at 3rd full ¶ starting with “The Applicant has…”). This is not persuasive because, as noted in the rejections of record, multi-dose protein formulations require antimicrobial preservatives to extend shelf-life, but antimicrobial preservatives (e.g., m-cresol) were 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, it is neither surprising nor unexpected that m-cresol can cause protein aggregation. In fact, the prior art of 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). As noted above, if protein aggregation was observed upon addition of m-cresol, then an artisan following the guidance of Hutchings and US’696 would solve this issue by adding an “organic modifier”, such as acetic acid “up to 200 mM” (see, e.g., US’696 at col. 27 at lines 46-54, col 30 at lines 10-30), exactly as taught, suggested, and disclosed by the prior art, wherein addition of acetic acid would necessarily lower the pH. Accordingly, adding m-cresol to act as an antimicrobial preservative, and then lowing pH by adding acetic acid to address precipitation, is not surprising or unexpected in view of the prior art of record.
Allegations that Rejection 01 does not describe “the detrimental effects of m-cresol” are not persuasive: Applicant alleges that the cited references in Rejection 01 do not describe the “deleterious effect on ZP1848 formulations . . . at higher pH values” of m-cresol” (see, e.g., Reply filed 7/24/2026 at 5 at final ¶, 6 at 1st partial and 1st and 2nd full ¶¶; see also id. at 7 at final ¶, addressing Hutchings; see also id. at 8 at penultimate ¶, suggesting unexpected results). This line of reasoning and arguments are not persuasive for several reasons:
First, such “deleterious effects” are not a claimed limitation. Therefore, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “deleterious effect on ZP1848 formulations . . . at higher pH values” of m-cresol”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Accordingly, there is no requirement under 35 USC 103 that prior art provide a description of the Applicant’s rationale for arriving at a claimed invention, so long as the claimed limitations are satisfied and obvious in view of the prior art.
Second, presumably Applicant is alleging that the Examiner did not rely upon the Applicant’s rationale for arriving at the instantly claimed invention in Rejection 01, but instead relied upon a different rationale as set forth at MPEP §§ 2143(I)(A), (C), (D), (F), (G), and MPEP § 2144.05(I)17. This rationale is not sufficient to rebut prima facie obviousness because, per MPEP § 2144(IV), the Examiner may rely upon a rationale that differs from the Applicant’s rationale, and “It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant”. Here, the prior art teaches the exact same components, for use at overlapping ranges and pH values, wherein each component merely performs its art-recognized function in combination as it does separately, and therefore the combination is obvious. This determination is consistent with the Court, which as stated that
"[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious."
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)).
Likewise, the Supreme Court has rejected rigid tests for obviousness and has emphasized that
[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”
KSR Int'l v. Teleflex Inc., 550 U.S. 398, 415 (2007), at 416.
And has also emphasized that
“If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.”
KSR Int'l v. Teleflex Inc., 550 U.S. 398, 415 (2007), at 417.
Here, all aspects of the claimed method were already known in the art, and all claimed values fall within routine and known concentration ranges of record, wherein each component merely performs it’s art-recognized function.
Third, if Applicant is attempting to again allege unexpected results commensurate in scope with the requirements of MPEP § 716.02, sufficient to rebut prima facie obviousness, then such arguments are not persuasive because data commensurate in scope with the requirements of MPEP § 716.02 have not been placed on record to date. 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)). However, in the instant case, the proffered data does not satisfy the requirements of MPEP § 716.02 at least because:
(A), no evidence of criticality of range has been established (see, e.g., MPEP § 716.02(d)(II)) by testing sufficient values beyond the claimed range. This is pertinent because the closest prior art of record literally identifies the same components at overlapping ranges, and overlapping pH values, wherein m-cresol was literally disclosed as an optionally present preservative.
(B) 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)).
(C), 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.
(D), Examiner acknowledges Applicants assertions that “Applicant disagrees that Hutchings sets an expectation that m-cresol is a causative agent of aggregation of ZP1848, as Hutchings is entirely directed to cytochrome c” (see, e.g., Reply filed 7/24/2026 at 7 to 8 at 1st full ¶), and alleges “Thus, the skilled person could not conclude….” (see id). This position is not persuasive because an artisan would readily appreciate that cytochrome c is used as a model protein to test and evaluate “antimicrobial preservative” effects on “protein formulations”, generally (see, e.g., Hutchings at title, abs, passim). Applicant provides no scientific or logical basis supported by objective evidence, which supports their position that an artisan would simply dismiss or ignore that Antimicrobial preservatives (“AP”, such as m-cresol) were already known to cause protein aggregation” in protein formulations (see Hutchings at title, abs, 373). Furthermore, Applicant fails to address the teachings of US’696, which explicitly teaches “preventing aggregation” in GLP-2 formulations can be achieved by “organic modifiers” such as acetic acid (see, e.g., US’696 at col. 27 at lines 46-54), the addition of which would predictably lower the pH value of GLP-2 formulations.
Allegations suggesting “skepticism of experts”: If Applicant’s statements amount to a suggestion of the existence of skepticism of experts that the Examiner’s position regarding Hutchings, US’696, protein aggregation caused by m-cresol, and reduction of such aggregation by acetic acid would be met with skepticism of experts (see, e.g., Reply filed 7/24/2026 at 7 to 8 at 1st full ¶), then such evidence should be filed per MPEP § 716.05 because evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. 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)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)), and no objective evidence rebutting this presumption has been placed on record to date.
Allegations suggesting “inoperability” or lack of enabling disclosure regarding a prior art reference: It is the Examiner’s understanding that Applicant’s statements amount to a suggestion that the prior art is not fully enabled or operable (see, e.g., Reply filed 7/24/2026 at 7 to 8 at 1st full ¶). If Applicant is attempting to allege that the prior art is not enabling or inoperable to reduce protein aggregation caused by antimicrobial preservatives (i.e., m-cresol) by adding an organic modifier, such as acetic acid (thereby lowing pH) as suggested and taught by the prior art, then Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. The Examiner’s position is that 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)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)). Accordingly, the Applicant has not satisfied their burden to rebut the presumption of operability of the prior art at this time (see, e.g., MPEP § 2121(I); MPEP § 716.07).
Accordingly, no evidence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been placed on record to date.
Accordingly, arguments alleging that the instant rejection(s) do not address the Applicant’s rationale for arriving at the claimed invention, unclaimed limitations referring to “deleterious effects”, or suggestions of unexpected results, have been fully considered but not found persuasive.
Allegation that US’403 does not teach all claimed limitations: It is the Examiner’s understanding that Applicant is alleging that US’403 does not teach that m-cresol should be included specifically at 3.15 mg/mL (see, e.g., Reply filed 7/24/2026 at 6 at 1st full ¶¶). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). US’403 has not been applied alone, and therefore arguments that it alone does not render the claim scope obvious are not relevant to the rejections of record.
Allegation that express teachings are required to support a determination of obviousness is not persuasive: It is the Examiner’s understanding that Applicant is alleging and suggesting that the cited references at Rejection 01 “do not provide express teaching toward the claimed invention which features specific values for each element of the formulation—there is therefore no guidance in the cited references to select the specific values …. as claimed” (see, e.g., Reply filed 7/24/2026 at 6 at 1st full ¶¶). This is not persuasive for the following reasons:
First, express teachings of specifically claimed values are not required to render a claimed invention obviousness (see, e.g., MPEP §§ 2144(I), (II), (III), 2144.01-2144.08), and the courts have explicitly stated "in considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom" (see, e.g., In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968); see also MPEP § 2144.01).
Second, here it is undisputed that the prior art of record teaches the combination of the same exact chemical compounds, for use in known methods, wherein the known compounds are taught for use at ranges that overlap the instantly claimed values. This is sufficient to support a determination of obviousness because where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists” (see, e.g., MPEP § 2144.05(I)). Accordingly, overlapping ranges is sufficient to support a determination of prima facie obviousness. No evidence of unexpected results commensurate in scope with MPEP § 716.02 sufficient to rebut such prima facie obviousness has been placed on record to date.
Third, if Applicant means to allege that the instant inventor(s) have recognized another advantage (e.g., avoiding “deleterious effects”) which would flow naturally from following the suggestion of the prior art, such advantage 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). Here, all elements were well-known in the prior art, taught for use together in pharmaceutical formulations, and all components fall within the concentration ranges explicitly taught, disclosed, and suggested by the prior art, wherein each element merely performs its art-recognized functionality in combination that it does alone. Accordingly, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (see, e.g., In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Accordingly, prima facie obviousness has been established; this determination may be rebutted by a proper showing of secondary considerations commensurate in scope with the requirements discussed at MPEP § 716.02.
Accordingly, all claimed limitations were fully considered and addressed, and a determination of prima facie obviousness was properly established in view of the prior art, and express teachings of specific values are not required to establish obviousness of values falling within known prior art ranges.
Applicant addresses Rejection 02 at page 9 (see, e.g., Reply filed 7/24/2026 at 9 at 1st to last ¶¶). It is the Examiner’s understanding that Applicant alleges that (A) “The ’696 does not describe formulations with any further granularity or guidance than the ‘403 patent” (see, e.g., Reply filed 7/24/2026 at 9 at 3rd full ¶); and (B) alleges that “basic salts of acetate are not agents that would reduce the pH of the formulation”, and therefore the “Office’s conclusion . . . is misguided” (see, e.g., Reply filed 7/24/2026 at 9 at 3rd full ¶). These arguments are not persuasive because
(A) It is the Examiner’s understanding that Applicant is alleging that US’696 does not teach that m-cresol should be included specifically at 3.15 mg/mL or otherwise teach the claimed inventions with sufficient “granularity or guidance” (see, e.g., Reply filed 7/24/2026 at 9 at 3rd full ¶). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). US’403 has not been applied alone, and therefore arguments that it alone does not render the claim scope obvious are not relevant to the rejections of record.
(B) Regarding the assertions regarding “basic salts of acetate… are not agents that would reduce the pH of the formulation” (see, e.g., Reply filed 7/24/2026 at 9 at 3rd full ¶), Examiner notes that Applicant appears to have inadvertently omitted the context of the full disclosure, which states “Organic modifiers for solubilization or preventing aggregation, such as ethanol, acetic acid or acetate and salts thereof may be provided in the pharmaceutical compositions” (see, e.g., US’696 at col. 27 at lines 45-55, emphasis added). Accordingly, US’696 teaches and discloses that “preventing aggregation” can be addressed by addition of “acetic acid . . . and salts thereof”, which includes both acetic acid, as well as “salts thereof”. Accordingly, the Applicant’s argument appears to erroneously attempt to dismiss, ignore, or omit the full guidance of the prior art, which in fact directs artisans to add acetic acid to reduce or prevent protein aggregation in GLP-2 formulations, which would predictably reduce the pH of the GLP-2 formulations (see, e.g., US’696 at col. 27 at lines 45-55, emphasis added). Critically, such added acetic acid was already accounted for by the primary reference, and is still permitted in the instant claims. Accordingly, Applicant’s arguments are not persuasive because they are premised upon an incomplete reading of the teachings of the prior art.
Accordingly, such arguments have been fully considered but not found persuasive.
Prima facie obviousness has been established: It is the Examiner’s understanding that Applicant fails to dispute, with specificity, 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.
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.
Examiner did not rely upon improper hindsight reasoning: It is the Examiner’s understanding that Applicant has previously alleged 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’06118 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’06119 at 13 at line 34 to page 14 at line 12, p. 20 at lines 17-25).
Zapadka et al.20 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.
Applicant's amendment necessitated the new or revised ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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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 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”.
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 See, e.g., Rowe at 203 at §6, 204 at §10, 205 at §18.
6 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”).
7 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.
8 See, e.g., US’039 at col. 29 at lines 15-21 and 50-55.
9 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”; cited in previous action.
10 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”.
11 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”
12 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 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.
16 See, e.g., US’039 at col. 29 at lines 15-21 and 50-55.
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 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).
19 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).
20 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”; cited in previous action.
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