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 .
Priority
Priority to US 63/726,872, filed 12/02/2024, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 12/24/2025, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-22, filed 6/4/2026, are pending. Claims 1-22 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
Response to Arguments
Applicant’s arguments, see Applicant Reply page 6, para. 2, filed 6/4/2026, with respect to the specification have been fully considered and are persuasive. The objection to the specification has been withdrawn.
Claim Rejections - 35 USC § 103
Response to Arguments
Applicant’s arguments, see Applicant Reply page 6, para. 6, filed 6/4/2026, with respect to the rejection of claims 1-22 under U.S.C. §103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made below.
New Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-22 are rejected under 35 U.S.C. 103 as being unpatentable over Craig et al. (US 20210338780, published 11/4/2021 in view of Falconer (Falconer, Robert J. Biotechnology advances 37.7: 107412. (2019)), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)) and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, amended claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Craig discloses a buffered liquid formulation comprising avexitide at a concentration of between 2-90 mg/mL (Craig et al., Claim 1).
Regarding the claimed concentration of about 90 mg/mL and 110 mg/mL, this range overlaps with the range disclosed by Craig. Craig also discloses a range of 30 mg/mL to 180 mg/mL in claim 26: “The method of any of claims 1-25, wherein the formulation comprises avexitide at a concentration from 30 mg/mL to 180 mg/mL; or from 2 mg/mL to 29 mg/mL.” This range also overlaps with the claimed range of about 90 mg/mL to 110 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding the sodium acetate buffer, Craig et al. discloses the usage of sodium acetate buffer in claim 31: “The method of any of claims 1 to 30, wherein the formulation comprises a sodium acetate buffer.” Craig also discloses the concentration range of: “In some embodiments, the physiologically acceptable buffer comprises an acetate buffer (e.g., sodium acetate or potassium acetate) at a concentration of about 5 mM to about 30 mM, e.g., about 10 mM to about 20 mM.” (Craig et al., para. [0076]). When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, these ranges overlap and are prima facie obvious.
Regarding the mannitol component, Craig discloses the use of a tonicity modifier in claim 32: “The method of any of claims 1 to 31, wherein the formulation comprises a tonicity modifier.” Craig also discloses the case wherein the tonicity modifier is mannitol in claim 33: “The method of claim 32, wherein the tonicity modifier comprises mannitol.”
Craig discloses the following concentration range for mannitol, which does not overlap with the present claim: “In some embodiments, the tonicity modifier comprises mannitol. In some embodiments, the mannitol is present at a concentration of about 40-50 mg/ml.” (Craig at al., para. [0081]).
However, the role of mannitol as a tonicity modifier results in mannitol being a result-effective variable: “The osmotic pressure of a therapeutic protein formulation should be close to being isotonic (approximately 290 mOsm/L). At osmotic pressures lower than 290 mOsm/L (hypotonic) red blood cells swell and can lyse. At osmotic pressures higher than 290 mOsm/L (hypertonic) red blood cells collapse as the water is drawn out of them. Isotonic formulations are desirable even for smaller subcutaneous injections as it can minimise tissue damage around the site of injection.
Commonly used tonicity modifiers used in excipients include NaCl, sucrose, trehalose, mannitol, glycerol and sorbitol.” (Falconer, page 2, col. 2, para. 7).
Consequently, a person of ordinary skill in the art would seek to optimize this variable and MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Regarding solution pH, Craig discloses that the formulation can have a pH of about 5.5 in claim 30 : “The method of any of claims 1 to 29, wherein the formulation has a pH of about 5.5.” This reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Craig does not disclose any specific osmolality values.
However, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the disclosed concentrations of Craig and Wang to arrive at the claimed invention.
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Craig because Craig discloses of the effectiveness of the formulation: “Overall, the strength and consistency of the data in aggregate combined with the tolerability and safety data demonstrate a clear and robust treatment benefit and support the continued development of avexitide for treatment of PBH.” (Craig et al., para. [0356].
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the avexitide concentration, sodium acetate concentration, and the pH are prima facie obvious and used in a formulation for the treatment of hyperinsulinemic hypoglycemia. The optimization of tonicity is routine in the art as described by Falconer and the osmolality disclosed by Wang is hypertonic, which is known to be frequently useful with high concentration biologics.
Therefore, claim 1 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.).”
The value of 90 mg/mL is within 10% of the claimed value “about 100 mg/mL” and therefore reads on the value as claimed.
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Consequently, claim 2 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Craig discloses that: “In some embodiments, the physiologically acceptable buffer comprises an acetate buffer (e.g., sodium acetate or potassium acetate) at a concentration of about 10 mM.” (Craig et al., para. [0076]).
Consequently, claim 3 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Craig discloses the following concentration range for mannitol, which does not overlap with the present claim: “In some embodiments, the tonicity modifier comprises mannitol. In some embodiments, the mannitol is present at a concentration of about 40-50 mg/ml.” (Craig at al., para. [0081]).
However, the role of mannitol as a tonicity modifier results in mannitol being a result-effective variable: “The osmotic pressure of a therapeutic protein formulation should be close to being isotonic (approximately 290 mOsm/L). At osmotic pressures lower than 290 mOsm/L (hypotonic) red blood cells swell and can lyse. At osmotic pressures higher than 290 mOsm/L (hypertonic) red blood cells collapse as the water is drawn out of them. Isotonic formulations are desirable even for smaller subcutaneous injections as it can minimise tissue damage around the site of injection.
Commonly used tonicity modifiers used in excipients include NaCl, sucrose, trehalose, mannitol, glycerol and sorbitol.” (Falconer, page 2, col. 2, para. 7).
Consequently, a person of ordinary skill in the art would seek to optimize this variable and MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Claim 4 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Craig discloses that the formulation can have a pH of about 5.5 in claim 30 : “The method of any of claims 1 to 29, wherein the formulation has a pH of about 5.5.” This reads on the claimed range of pH values.
Consequently, claim 5 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Craig, Falconer, Wang, and Challener for the claimed method because the formulation of Craig is used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Craig claim 8 discloses the following dose range: “The method of claim 1, wherein the avexitide is administered at a total daily dose from about 40 mg to about 120 mg; or from 30 mg-60 mg BID, or from 60 mg-120 mg QD; or from about 45 mg BID, or about 35-55 mg BID.”
These ranges substantially overlap and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
. Consequently, claim 17 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Craig claim 12 discloses: “The method of claim 2, wherein the avexitide is administered at a total daily dose of about 60 or about 120 mg.”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over Craig et al. in view of Falconer, Wang, and Challener and rejected.
Claims 1-22 are rejected under 35 U.S.C. 103 as being unpatentable over Xiong et al. 2 (U.S. Patent No. 11,738,086, granted 8/29/2023), in view of Craig et al. (US 202110338780, published 11/4/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)) and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 11: “The method of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 2 reads on this range.
Regarding the mannitol component, Xiong et al. 2 discloses the use of mannitol as a tonicity modifier in claim 15: “The method of claim 14, wherein the tonicity modifier comprises mannitol.” Xiong et al. 2 also discloses: ”The method of claim 14, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 16. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 13: “The method of claim 12, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the osmolality range of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Xiong et al. 2 does not specifically disclose a concentration of avexitide. However, Craig discloses a buffered liquid formulation comprising avexitide at a concentration of between 2-90 mg/mL (Craig et al., Claim 1).
Regarding the claimed concentration of about 90 mg/mL and 110 mg/mL, this range overlaps with the range disclosed by Craig. Craig also discloses a range of 30 mg/mL to 180 mg/mL in claim 26: “The method of any of claims 1-25, wherein the formulation comprises avexitide at a concentration from 30 mg/mL to 180 mg/mL; or from 2 mg/mL to 29 mg/mL.” This range also overlaps with the claimed range of about 90 mg/mL to 110 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the disclosed concentrations of Craig, Wang, Challener and Xiong et al. 2 to arrive at the claimed invention.
A person of ordinary skill in the would be motivated to use the formulation of the method as disclosed by Xiong et al. 2 with the disclosure of Craig because both are directed to methods and compositions for treating hyperinsulinemic hypoglycemia using the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the osmolality and the pH are prima facie obvious and used in a formulation for the treatment of hyperinsulinemic hypoglycemia as disclosed by Xiong et al. 2. The concentration of avexitide disclosed by Craig is used for the same purpose, treating hyperinsulinemic hypoglycemia, and therefore a person of ordinary skill in the art would expect that concentration to be efficacious with the method of Xiong et al. 2. Also, the osmolality disclosed by Wang is hypertonic, which is known to be frequently useful with high concentration biologics.
Therefore, claim 1 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.).”
The value of 90 mg/mL taught by Craig et al. is within 10% of the claimed value “about 100 mg/mL” and therefore reads on the value as claimed.
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Consequently, claim 2 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 11 of Xiong et al. 2 discloses: “The method of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 2 discloses: ”The method of claim 14, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 16.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 13: “The method of claim 12, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 2 discloses in claim 17: “The method of claim 16, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above. The resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 2 and Craig for the claimed method because the formulations of Xiong et al. 2 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 2 claim 4 discloses the following dose range: “The method of any of claim 1, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 2 in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected..
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
. Consequently, claim 17 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 4 of Xiong et al. 2 discloses: “The method of any of claim 1, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over Xiong et al. 2 in view of Craig et al., Wang, and Challener and rejected.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021) in view of Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)) and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 3 reads on this range.
Regarding the mannitol component, Xiong et al. 3 discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” Xiong et al. 3 also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Regarding the claimed concentration of about 90 mg/mL and 110 mg/mL, Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Xiong et al. 3 because Xiong et al. 3 is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, the pH, and the osmolality are all prima facie obvious. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions. Also, Wang discloses that high tonicity formulation are frequently used with high concentration biologics for stability and efficacy purposes.
Therefore, claim 1 is obvious over Xiong et al. 3 in view of Wang and Callener and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over Xiong et al. 3 in view of Wang and Callener and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of Xiong et al. 3 discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over Xiong et al. 3 in view of Wang and Callener and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 3 discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over Xiong et al. 3 in view of Wang and Callener and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over Xiong et al. 3 in view of Wang and Callener and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 3 discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over Xiong et al. 3 in view of Wang and Callener and rejected.
Claims 7-22 are rejected under 35 U.S.C. 103 as being unpatentable over Xiong et al. 2 ( U.S. Patent No. 11,020,484, granted 6/1/2021) Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)) and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)) as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘484 does not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 3 and Craig for the claimed method because the formulations of Xiong et al. 3 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 3 claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 3 in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
. Consequently, claim 17 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of Xiong et al. 3 discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over Xiong et al. 3 in view of Wang and Challenger as applied to claim 1, further in view of Craig et al. and rejected.
Examiner’s Note
As noted above, these are new rejections in view of the amendments. However, the issue of mannitol concentration was raised in Applicant’s Reply, see page 11, para. 6, filed 6/4/2026:
“The cited references also do not specifically identify the presently claimed mannitol
concentration of about 18 mg/mL to about 25 mg/mL in the claimed avexitide formulation. The Office's position appears to rest on the premise that, because mannitol can function as a tonicity modifier, its concentration would have been a result-effective variable subject to routine optimization. But the cited references do not direct the skilled artisan to the presently claimed mannitol range. Instead, when mannitol is specifically discussed, the cited references point to materially higher mannitol concentrations.” (Applicant Reply, page 11, para. 6).
Examiner agrees that the recited mannitol concentration is not recited. However, explicit disclosure is a requirement of a rejection under U.S.C. 102, not U.S.C. 103. The issue of mannitol was addressed above by the routine optimization of a person of ordinary skill in the art.
MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
This logic is provided because the nature of this rejection has not changed in the new, updated rejections above and Examiner wishes to advance prosecution on this topic.
Double Patenting
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 15, para. 5, filed 6/4/2026, with respect to the rejection(s) of claims 1-22 for nonstatutory double patenting have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new grounds of rejection are made below.
New Rejections - Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 8, 11, and 15-17 of U.S. Patent No. 11,738,086, granted 8/29/2023, in view of Craig et al. (US 202110338780, published 11/4/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)) and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022))..
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Regarding the sodium acetate buffer, the ‘086 patent discloses the usage of sodium acetate buffer at 10 mM in claim 11: “The method of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in the ‘086 patent reads on this range.
Regarding the mannitol component, the ‘086 patent discloses the use of mannitol as a tonicity modifier in claim 15: “The method of claim 14, wherein the tonicity modifier comprises mannitol.” The ‘086 patent also discloses: ”The method of claim 14, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 16. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, the ‘086 patent discloses that the formulation can have a pH of about 5.5 in claim 13: “The method of claim 12, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, the ‘086 patent and Craig do not disclose any specific osmolality values.
However, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
The ‘086 patent does not specifically disclose a concentration of avexitide. However, Craig discloses a buffered liquid formulation comprising avexitide at a concentration of between 2-90 mg/mL (Craig et al., Claim 1).
Regarding the claimed concentration of about 90 mg/mL and 110 mg/mL, this range overlaps with the range disclosed by Craig. Craig also discloses a range of 30 mg/mL to 180 mg/mL in claim 26: “The method of any of claims 1-25, wherein the formulation comprises avexitide at a concentration from 30 mg/mL to 180 mg/mL; or from 2 mg/mL to 29 mg/mL.” This range also overlaps with the claimed range of about 90 mg/mL to 110 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the discloses concentrations of Craig and the ‘086 patent to arrive at the claimed invention.
A person of ordinary skill in the would be motivated to use the formulation of the method as disclosed by the ‘086 patent with the disclosure of Craig because both are directed to methods and compositions for treating hyperinsulinemic hypoglycemia using the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration and the sodium acetate concentration, and the pH are prima facie obvious and used in a formulation for the treatment of hyperinsulinemic hypoglycemia as disclosed by the ‘086 patent. The concentration of avexitide disclosed by Craig is used for the same purpose, treating hyperinsulinemic hypoglycemia, and therefore a person of ordinary skill in the art would expect that concentration to be efficacious with the method of the ‘086 patent. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well.
Therefore, claim 1 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.).”
The value of 90 mg/mL taught by Craig et al. is within 10% of the claimed value “about 100 mg/mL” and therefore reads on the value as claimed.
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Consequently, claim 2 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 11 of the ‘086 patent discloses: “The method of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
The ‘086 patent discloses: ”The method of claim 14, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 16.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. The ‘086 patent discloses that the formulation can have a pH of about 5.5 in claim 13: “The method of claim 12, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
The ‘086 patent discloses in claim 17: “The method of claim 16, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above. The resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of the ‘086 patent and Craig for the claimed method because the formulations of the ‘086 patent and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
The ‘086 patent claim 4 discloses the following dose range: “The method of any of claim 1, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
. Consequently, claim 17 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 4 of the ‘086 patent discloses: “The method of any of claim 1, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘086 patent in view of Craig et al., Wang et al., and Challener et al. and rejected.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 9-11, and 13 of U.S. Patent No. 11,020,484, granted 6/1/2021 in view of Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)) and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Regarding the sodium acetate buffer, the ‘484 patent discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in the ‘484 patent reads on this range.
Regarding the mannitol component, the ‘484 patent discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” The ‘484 patent also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, the ‘484 patent discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Regarding the claimed concentration of about 90 mg/mL and 110 mg/mL, the ‘484 patent claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by the ‘484 patent because the ‘484 patent is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, and the pH are all prima facie obvious. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions.
Therefore, claim 1 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
The ‘484 patent claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. and rejected. .
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of the ‘484 patent discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
The ‘484 patent discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. The ‘484 patent discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
The ‘484 patent discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. and rejected.
Claims 7-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 9-11, 13, and 24 of U.S. Patent No. 11,020,484, granted 6/1/2021 in view of Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)) and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)), as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘484 does not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of the ‘484 patent and Craig for the claimed method because the formulations of the ‘484 patent and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
The ‘484 patent claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
. Consequently, claim 17 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of the ‘484 patent discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘484 patent in view of Wang et al. and Challener et al. as applied to claim 1 above, further in view of Craig et al. and rejected.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,660,937, issued 5/26/2020, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Claim 1 of the ‘937 patent discloses treating a patient with hyperinsulinemic hypoglycemia with exendin (9-39), but fails to disclose the exact composition disclosed by claim 1.
However, Xiong et al. 3 discloses the following:
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 3 reads on this range.
Regarding the mannitol component, Xiong et al. 3 discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” Xiong et al. 3 also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Regarding the claimed concentration of about 90 mg/mL and 110 mg/mL, Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Xiong et al. 3 with the method of claim of the ‘937 patent because Xiong et al. 3 is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, and the pH are all prima facie obvious. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions.
Therefore, claim 1 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of Xiong et al. 3 discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 3 discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 3 discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. and rejected.
Claims 7-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,660,937, issued 5/26/2020, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021) Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)) as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘937 patent and Xiong et al. 3 do not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 3 and Craig for the claimed method because the formulations of Xiong et al. 3 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 2 claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 3 in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
Consequently, claim 17 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of Xiong et al. 3 discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘937 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,993,992, issued 5/4/2021, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between abo1ut 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Claim 1 of the ‘992 patent discloses treating a patient with hyperinsulinemic hypoglycemia with exendin (9-39), but fails to disclose the exact composition disclosed by claim 1.
However, Xiong et al. 3 discloses the following:
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 3 reads on this range.
Regarding the mannitol component, Xiong et al. 3 discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” Xiong et al. 3 also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Regarding the claimed concentration of about 90 mg/mL and 110 mg/mL, the ‘484 patent claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding the claimed concentration of about 90 mg/mL and 110 mg/mL, Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Xiong et al. 3 with the method of claim of the ‘992 patent because Xiong et al. 3 is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, and the pH are all prima facie obvious. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions.
Therefore, claim 1 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of Xiong et al. 3 discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 3 discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 3 discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Claims 7-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,993,992, issued 5/4/2021, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)) as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘992 patent and Xiong et al. 3 do not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 3 and Craig for the claimed method because the formulations of Xiong et al. 3 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 2 claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 3 in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘992 patent in view of Xiong et al. 3 and further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
Consequently, claim 17 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of Xiong et al. 3 discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘992 patent in view of Xiong et al. 3, Wang et al., Challener et al., and further in view of Craig et al. and rejected.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,622,995, issued 4/11/2023, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Claim 1 of the ‘995 patent discloses treating a patient with hyperinsulinemic hypoglycemia with exendin (9-39), but fails to disclose the exact composition disclosed by claim 1.
However, Xiong et al. 3 discloses the following:
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 3 reads on this range.
Regarding the mannitol component, Xiong et al. 3 discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” Xiong et al. 3 also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Xiong et al. 3 with the method of claim of the ‘995 patent because Xiong et al. 3 is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, and the pH are all prima facie obvious. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions.
Therefore, claim 1 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of Xiong et al. 3 discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 3 discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 3 discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Claims 7-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,622,995, issued 4/11/2023, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)). as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘995 patent and Xiong et al. 3 do not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 3 and Craig for the claimed method because the formulations of Xiong et al. 3 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 2 claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 3 in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
Consequently, claim 17 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of Xiong et al. 3 discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘995 patent in view of Xiong et al. 3, Wang et al, and Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,220,444, issued 2/11/2025, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Claim 1 of the ‘444 patent discloses treating a patient with hyperinsulinemic hypoglycemia with exendin (9-39), but fails to disclose the exact composition disclosed by claim 1.
However, Xiong et al. 3 discloses the following:
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 3 reads on this range.
Regarding the mannitol component, Xiong et al. 3 discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” Xiong et al. 3 also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Xiong et al. 3 with the method of claim of the ‘444 patent because Xiong et al. 3 is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, and the pH are all prima facie obvious. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions.
Therefore, claim 1 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of Xiong et al. 3 discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 3 discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 3 discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Claims 7-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,220,444, issued 2/11/2025, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)) as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘444 patent and Xiong et al. 3 do not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 3 and Craig for the claimed method because the formulations of Xiong et al. 3 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 2 claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 3 in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
Consequently, claim 17 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of Xiong et al. 3 discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘444 patent in view of Xiong et al. 3, Wang et al, Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,639,354, issued 5/5/2020, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Claim 1 of the ‘354 patent discloses treating a patient with hyperinsulinemic hypoglycemia with exendin (9-39), but fails to disclose the exact composition disclosed by claim 1.
However, Xiong et al. 3 discloses the following:
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 3 reads on this range.
Regarding the mannitol component, Xiong et al. 3 discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” Xiong et al. 3 also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Xiong et al. 3 with the method of claim of the ‘354 patent because Xiong et al. 3 is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, and the pH are all prima facie obvious. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions.
Therefore, claim 1 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of Xiong et al. 3 discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 3 discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 3 discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. and rejected.
Claims 7-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,639,354, issued 5/5/2020, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)) as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘354 patent and Xiong et al. 3 do not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 3 and Craig for the claimed method because the formulations of Xiong et al. 3 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 2 claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 3 in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
Consequently, claim 17 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of Xiong et al. 3 discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘354 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1 , and further in view of Craig et al. and rejected.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,617,782, issued 4/4/2023, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Claim 1 of the ‘782 patent discloses treating a patient with hyperinsulinemic hypoglycemia with exendin (9-39), but fails to disclose the exact composition disclosed by claim 1.
However, Xiong et al. 3 discloses the following:
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 3 reads on this range.
Regarding the mannitol component, Xiong et al. 3 discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” Xiong et al. 3 also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Xiong et al. 3 with the method of claim of the ‘782 patent because Xiong et al. 3 is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, and the pH are all prima facie obvious. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions.
Therefore, claim 1 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al, Challener et al., and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al, Challener et al., and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of Xiong et al. 3 discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al, Challener et al., and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 3 discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al, Challener et al., and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al, Challener et al., and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 3 discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al, Challener et al., and rejected.
Claims 7-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,617,782, issued 4/4/2023, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)). as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘782 patent and Xiong et al. 3 do not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 3 and Craig for the claimed method because the formulations of Xiong et al. 3 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 2 claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 3 in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
Consequently, claim 17 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of Xiong et al. 3 discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘782 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim 1, and further in view of Craig et al. and rejected.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,102,663, issued 10/1/2024, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)).
Regarding claim 1, claim 1 recites a formulation comprising avexitide or a pharmaceutically acceptable salt thereof at a concentration between about 90 mg/mL and 110 mg/mL, sodium acetate trihydrate at a concentration between about 1 mg/mL and about 1.5 mg/mL, and mannitol at a concentration between about 18 mg/mL and about 25 mg/mL, wherein the formulation has a pH of about 5.2 to about 5.7, and wherein the formulation has an osmolality of 305 mOsm/kg to 380 mOsm/kg.
Claim 1 of the ‘663 patent discloses treating a patient with hyperinsulinemic hypoglycemia with exendin (9-39), but fails to disclose the exact composition disclosed by claim 1.
However, Xiong et al. 3 discloses the following:
Regarding the sodium acetate buffer, Xiong et al. 2 discloses the usage of sodium acetate buffer at 10 mM in claim 5: “The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.” When converted to mM concentration, the claimed sodium acetate trihydrate buffer has a range of 7.3 mM to 11.0 mM. Therefore, the value disclosed in Xiong et al. 3 reads on this range.
Regarding the mannitol component, Xiong et al. 3 discloses the use of mannitol as a tonicity modifier in claim 9: “The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.” Xiong et al. 3 also discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Regarding solution pH, Xiong et al. 2 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Regarding the claimed osmolality of 305 mOsm/kg to 380 mOsm/kg, Wang discloses that this is a hypertonic solution range: “Human plasma has an osmolality of about 0.3 Osm/kg (300 mOsm/kg), therefore a 0.15 mol/kg NaCl solution may be said to be isotonic with plasma, assuming that neither Na+ nor Cl− can cross cell membranes freely (almost true). Solutions having a greater (or lower) osmolality than 300 mOsm/kg are hypertonic (or hypotonic).” (Wang et al., page 309, col. 2, para. 3).
Wang also discloses that hypertonic solutions, while not ideal, are sometimes necessary in the case of high concentration biologics: “The osmolality of an injectable product would ideally be the same or similar to that of the body fluid. In many cases, however, hypertonic (or in rare cases, hypotonic) drug product formulations have to be developed. This is because different types and amounts of formulation excipients are needed for drug efficacy, safety and/or stability. This is especially the case for high-concentration biological products, which may need excessive amount of stabilizers in a product formulation. Some commercial product solutions for intravenous injection were found to be extremely hypertonic with an osmolality of >>1000 mOsm/kg (e.g., digoxin, phenytoin, phenobarbital, etc.). (Wang et al., page 309, col. 1, para. 2).
Challener discloses that biological formulation with 100 mg/mL or more concentration are generally considered high-concentration: ““Approximately one-third of all FDA-approved monoclonal antibody (mAb) products comprise high-concentration formulations (>100mg/mL), with about three-quarters of those approved since 2015,” she notes (2).” (Challenger et al., page 2, para. 4).
The disclosure of Wang creates a range of greater than 300 mOsm/kg to at least 1000 mOsm/kg. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
A person of ordinary skill in the would be motivated to use the formulation as disclosed by Xiong et al. 3 with the method of claim of the ‘663 patent because Xiong et al. 3 is directed to the same protein, avexitide (exendin 9-39).
Furthermore, a person of ordinary skill in the art would be motivated to reference the osmolality of Wang because Challener shows that this claim reads on high concentration biologic drugs and that high tonicity formulations are frequently with high concentration biologics for stability, safety, and efficacy purposes.
A person of ordinary skill in the art would have a reasonable expectation of success because as described above, the mannitol concentration, the sodium acetate concentration, the avexitide concentration, and the pH are all prima facie obvious. Wang discloses that the concentration of the avexitide renders the osmolality of the composition obvious as well. These compositions involve the same protein, avexitide, and therefore would be expected to work in the same buffer conditions.
Therefore, claim 1 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites the case wherein the formulation comprises the avexitide or the pharmaceutically acceptable salt thereof at a concentration of about 100 mg/mL.
MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)
Xiong et al. 3 claim 13 discloses: “The liquid pharmaceutical formulation of claim 1, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 10 mg/ml to about 120 mg/ml.”
Consequently, claim 2 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Claim 3 further recites the case wherein the formulation comprises sodium acetate trihydrate at a concentration of about 1.36 mg/mL. 1.36 mg/mL of sodium acetate trihydrate converts to a concentration of 10 mM. Claim 5 of Xiong et al. 3 discloses: “ The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.”
Consequently, claim 3 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites the case wherein the formulation comprises mannitol at a concentration of about 19 mg/mL.
Xiong et al. 3 discloses: ” The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.” in claim 10.
The value of 19 mg/mL is 5% different than about 20 mg/mL and therefore reads on the value as claimed. This range overlaps the claimed mannitol range and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Even if this were not the case, MPEP 2144.05(I) further states: “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Claim 4 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites the case wherein the formulation has a pH of about 5.4 or about 5.5. Xiong et al. 3 discloses that the formulation can have a pH of about 5.5 in claim 7: “The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.” This value reads on the claimed range of pH values.
Consequently, claim 5 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case wherein the formulation has an osmolality of about 330 mOsm/kg.
Xiong et al. 3 discloses in claim 11: “The liquid pharmaceutical formulation of claim 10, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.”
As described above, osmolality is a results-effective variable. Therefore, a person of ordinary skill in the art would optimize this variable. MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Consequently, claim 6 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., and Challener et al. and rejected.
Claims 7-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,102,663, issued 10/1/2024, in view of Xiong et al. 3 (U.S. Patent No. 11,020,484, granted 6/1/2021), Wang et al. (Wang, Wei. 490.1-2: 308-315 (2015)), and Challener et al. (Challener, Cynthia A. BioPharm Int 35.3 (2022)) as applied to claim 1 above, further in view of Craig et al. (US 202110338780, published 11/4/2021).
Regarding claim 7, claim 7 recites a method of treating post-bariatric hypoglycemia (PBH) in a subject in need thereof, comprising administering to the subject the formulation of claim 1, and wherein the method reduces a composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline.
The formulation of claim 1 is obvious as described above.
The ‘663 patent and Xiong et al. 3 do not specifically disclose these results from the administration of the formulation of claim 1.
However, the resulting formulation can injected into a subject, at which point the formulation is diluted into the blood stream. Consequently, trial results from Craig are reasonably pertinent to any formulations that can read on claim 1.
Craig discloses the following definitions for hypoglycemia events:
PNG
media_image1.png
262
735
media_image1.png
Greyscale
(Craig et al., page 22, Table 10).
Craig also discloses that the formulation can reduce the mean events for both level 2 events (Rate of clinically important hypoglycemia) and level 3 (Third-party assistance) as shown in Table 8:
PNG
media_image2.png
664
835
media_image2.png
Greyscale
(Craig et al., page 21, Table 8).
A person of ordinary skill in the art would have a reasonable expectation of success using the formulation of Xiong et al. 3 and Craig for the claimed method because the formulations of Xiong et al. 3 and Craig are both used to treat hyperinsulinemic hypoglycemia and the data from Craig shows that such a formulation reduces level 2 and level 3 events.
Consequently, claim 7 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 8, claim 7 is obvious as described above. Claim 8 further recites the case wherein the method comprises administering the formulation at a dose of 50 mg to 150 mg of the avexitide or the pharmaceutically acceptable salt thereof.
Xiong et al. 2 claim 24 discloses the following dose range: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily.”
This range substantially overlaps and MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 8 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 9, claim 7 is obvious as described above. Claim 9 further recites the case wherein the subject has undergone bariatric surgery at least 12 months prior to administration.
Craig discloses that the subjects in question had a minimum of 16 months since surgery:
PNG
media_image3.png
459
749
media_image3.png
Greyscale
(Craig, page 17, Table 5).
Consequently, claim 9 is obvious over Xiong et al. 3 in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 10, claim 9 is obvious as described above. Claim 10 further recites the case wherein the bariatric surgery is Roux-en-Y gastric bypass or vertical sleeve gastrectomy.
The surgery referenced by Craig Table 5 is Roux-en-Y gastric bypass surgery: “Inclusion criteria included, ability to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, procedures related to the use of the CGM device, and other study evaluations and procedures, and provide written informed consent; 18-65 years old; a body mass index (BMI) of up to 40 kg/m2; a stable body weight, i.e., not varying by >5% for at least 4 months; a documented Roux-en-Y gastric bypass (RYGB) surgery performed ≥12 months before the start of screening.” (Craig et al., page 12, para. [0192]).
Consequently, claim 10 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 11, claim 7 is obvious as described above. Claim 11 further recites the case wherein the subject has experienced at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
Craig discloses a subject that experienced four or more events that required help from a third party in a two-week period. This necessarily fulfills the element of at least three hypoglycemic events during a 3-week window prior to administration, wherein at least two of the at least three hypoglycemic events are Level 2 or greater in severity, and wherein at least one of the at least three hypoglycemic events is Level 3.
PNG
media_image4.png
810
540
media_image4.png
Greyscale
(Craig et al, page 22, Table 9).
Consequently, claim 11 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 12, claim 7 is obvious as described above. Claim 12 further recites the case wherein the subject has refractory PBH.
Craig discloses that at least one subject has refractory PBH: “Table 5 describes the severity of the disorder of the patients enrolled in the Phase 2 clinical trial described above. The study enrolled patients with severe, refractory post-bariatric hypoglycemia. Nearly half of all participants (44.4%) reported a history of loss of consciousness, 11.1% reported a history of seizure, and 16.7% reported a history of hospitalization due to PBH. Ninety-five percent of participants reported daily or weekly symptoms of hypoglycemia. All patients were refractory to dietary intervention and 83% were refractory to medical nutrition therapy, with 3 study participants resorting to surgical interventions for treatment of severe refractory PBH.” (Craig et al., page 16, para. [0265]).
Consequently, claim 12 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 13, claim 7 is obvious as described above. Claim 13 further recites the case wherein Level 2 hypoglycemia events are measured by self-monitoring of blood glucose (SMBG) and/or continued glucose monitoring (CGM).
Craig discloses that hypoglycemic events are measured by CGM: “FIG. 6 demonstrates glycemic improvements in the outpatient setting showing that there is a reduction in diurnal percent time and number of episodes<70 and <55 mg/dL as measured by CGM. Diurnal as used herein is 8 AM to midnight. Episodes are per 14-day period, and are defined as CGM values sustained below threshold for at least 10 min within in a 3-hour period. These results collected by blinded CGM corroborated both the glycemic benefits observed during in-clinic MMTT assessments, as well as the clinical and metabolic improvements as captured by the patient eDiary, overall demonstrating a reduction in biochemical and symptomatic hypoglycemia during both dosing regimens of avexitide treatment as compared to placebo.” (Crag et al., page 17, para. [0268]).
Consequently, claim 13 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 14, claim 7 is obvious as described above. Claim 14 further recites the case wherein the method reduces the composite rate of Level 2 hypoglycemia events and Level 3 hypoglycemia events in the subject relative to baseline by at least about 10%.
Table 8 of Craig, shown above, shows a decrease of level 3 (Third-party assistance) events by more than 50% and level 2 events (Rate of clinically important hypoglycemia) by more than 33% (Craig et al., page 21, Table 8).
Consequently, claim 14 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 15, claim 7 is obvious as described above. Claim 15 further recites the case wherein the method further reduces Level 1 hypoglycemia events in the subject relative to baseline and/or dietary liberalization in the subject relative to baseline.
Table 8 of Craig, shown above, shows a decrease in level 1 (Rate of hypoglycemia) events relative to baseline. (Craig et al., page 21, Table 8).
Consequently, claim 15 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 16, claim 7 is obvious as described above. Claim 16 further recites the case wherein the method reduces the percent time with glucose levels less than about 70 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 70 mg/dL:
PNG
media_image5.png
374
538
media_image5.png
Greyscale
(Craig et al., page 16, Table 3).
Consequently, claim 16 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 17, claim 7 is obvious as described above. Claim 17 further recites the case wherein the method reduces the percent time with glucose levels less than about 54 mg/dL for the subject relative to baseline.
Craig discloses that the formulation reduces the percent time with glucose levels less than about 54 mg/dL, as shown in Table 3 above (Craig et al., page 16, Table 3).
Consequently, claim 17 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the method comprises administering about 80 mg to about 100 mg of the avexitide or the pharmaceutically acceptable salt thereof per day.
Claim 24 of Xiong et al. 3 discloses: “The method of any of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a dosage of about 30 mg to about 75 mg once daily (QD).”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 18 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered once per day at a dose of about 90 mg.
Craig claim 15 discloses: “The method of claim 1, wherein the avexitide is administered at 45 mg-120 mg QD, and wherein the subject is required to fast after dosing or to delay the first meal of the day.”
This range contains the presently claimed amount. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 20, claim 7 is obvious as described above. Claim 20 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered at least about 30 minutes to about 90 minutes before a meal.
Craig claim 16 discloses: “The method of claim 15, wherein the delay is from between about 30 minutes to about 1.5 hours.”
Consequently, claim 20 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Claim 21 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.5 mL to about 1.5 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml…”
This range overlaps the presently claimed range. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 21 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Regarding claim 22, claim 21 is obvious as described above. Claim 22 further recites the case wherein the avexitide or the pharmaceutically acceptable salt thereof is administered subcutaneously in a total volume of about 0.9 mL.
Craig claim 61 discloses: “The method of claim 1, wherein the avexitide is administered in a total volume ranging from 0.25-2.0 ml; or in a total volume ranging from about 0.05-0.1 ml; or in an injection volume ranging from 0.25-1.5 ml, or from 0.5-1 ml, or from 0.7-1 ml, or from 0.05-0.1 ml.”
This range, specifically, 0.7-1 ml, contains the volume of 0.9 mL. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 22 is obvious over the ‘663 patent in view of Xiong et al. 3, Wang et al., Challener et al. as applied to claim1, and further in view of Craig et al. and rejected.
Conclusion
No claim is allowed.
Claims 1-22 are rejected.
Applicant's amendment necessitated the new grounds 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 David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
Prosecution Insights