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 .
Response to Amendment
This office action is responsive to the amendment filed on 27 March 2026. As directed by the amendment: claim 1 has been amended, claims 2-5, 10-26, 31-41, 43-56, and 60-61 have been or remain canceled. Thus claims 1, 6-9, 27-30, 42, 57-59, and 62-63 are presently pending in this application.
Response to Arguments
Applicant's arguments filed 27 March 2026 have been fully considered but they are not persuasive.
On page 5 of Remarks, applicant describes the amendment to state with more particularity that octreotide or diazoxide is not administered to the subject at any time in the claimed method.
The examiner agrees that Lord discloses administering diazoxide at some point before beginning a method of administering glucagon and glucose to determine the efficacy of diazoxide, however, a reasonable interpretation of the amended limitation does not exclude this. The claim does not specify a time-frame for the method, with a start and an end point. Without a start and end, and as outlined in the 112(b) rejection below, it is unclear when the limitation “wherein the subject is not administered octreotide or diazoxide” is implemented or when this is restricted to, and as outlined in the 112(a) rejection below, there is not support in the written description for not administering octreotide or diazoxide over an open-ended timeframe. Lord teaches stopping diazoxide if the patient is diazoxide unresponsive and recommends against octreotide as a pre-operative treatment, so Lord teaches not administering diazoxide or octreotide during a method that starts with administration of glucagon and ends with the administration of dextrose at a lower GIR. This appears to be the same as how the method is implemented in Example 2 ([0112]) of the instant application.
Applicant argues on page 9 of Remarks that Lord would have discouraged a skilled artisan from even attempting further optimization with glucagon to lower the GIR by stating “[t]rials of glucagon as a subcutaneous infusion through a pump were largely unsuccessful due to the drug’s lack of stability in solution.”
The examiner respectfully disagrees. The Lord reference is used as a secondary reference to Prestrelski which discloses a stabilized glucagon ([0010] “The solution is premised on using stable glucagon containing compositions in combination with pump-based delivery systems”), so when the references are considered in combination, one of ordinary skill would be able to consider glucagon’s lack of stability in solution as no longer an issue. Further, while Lord explains a downside of using glucagon in a pump, Lord does not teach away from using glucagon altogether.
Applicant argues on page 9 that Lord’s only express disclosure of GIR is on page 5, Table 1 (GIR > 10 mg/kg/min) and is in connection with criteria for diagnosing hyperinsulinism, and nothing in Lord would have led a skilled artisan to even try “routine optimization” to achieve the claimed methods. Applicant argues that based on the teachings of Lord of the use of diazoxide and discouraging further research with glucagon, a skilled artisan would not have attempted to achieve the claimed method absent the benefit of hindsight gleaned from Applicant’s disclosure. Applicant argues that Lord would not have offered any guidance to the skilled artisan about when the glucose should have been administered relative to the administration of the glucagon.
The examiner respectfully disagrees. As included in the rejection of claim 1, Lord recites on page 6 “Glucagon can be used as a continuous intravenous infusion of 1 mg/day to lower glucose infusion rate requirements in infants awaiting surgery.” (emphasis added). This indicates glucose is infused, then glucagon is administered and the glucose infusion rate then is lowered. Clinicians routinely titrate the glucose infusion rate depending on the needs of the patient which will vary by patient. The Lord reference discusses lowering a GIR with administration of glucagon, and because patients will usually need different GIRs after glucagon administration this would just be a lower GIR than initially given. Hyperinsulinism is a prerequisite for this treatment so the GIR is initially over 10 mg/kg/min to identify the condition (and in some cases lower as noted by the asterisk under Table 1), then the actual GIR any given patent needs after the glucagon is administered would be varied but it would be obvious for the lowered GIR to be below 7 mg/kg/min as routine optimization when glucagon results in a lower GIR. Additionally, the glucagon is being administered in the same way as that of the instant application, so the resulting GIR could also be assumed to be inherent as the glucagon of modified Prestrelski would interact with a patient in the same way, reducing glucose needs, as the glucagon of the instant application.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6-9, 27-30, 42, 57-59, and 62-63 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites “wherein the subject is not administered octreotide or diazoxide”. This negative limitation is not limited by any specific time frame and the full scope includes not administering octreotide or diazoxide ever. There is no written description to support not administering octreotide or diazoxide over the course of the patient’s entire life, weeks, days, hours… or any specific timeframe. In contrast, paragraph [0112] of the instant application describes an example in a clinical study: “Patients <1 year of age with CHI that requires glucose infusion to prevent hypoglycemia and that are non-responsive to diazoxide.” The patients would have to have been administered diazoxide in order to determine that they are non-responsive. Further an originally presented claim 52 recites administering diazoxide or octreotide or a combination thereof. As such, while there is adequate support for not administering octreotide or diazoxide from the administration of the first composition in step (a) through the subsequent administration of second composition in step (b), there is not adequate support for not administering octreotide or diazoxide with an open-ended timeframe.
Claims 6-9, 27-30, 42, 57-59, and 62-63 are rejected as being dependent on, and failing to cure the deficiencies of, rejected independent claim 1.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6-9, 27-30, 42, 57-59, and 62-63 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “wherein the subject is not administered octreotide or diazoxide”. As there is no time-frame for the negative limitation, this is excessively broad and indistinct. Without a specific time-frame, the patient would not ever be administered octreotide or diazoxide. Applicant states in Remarks that octreotide or diazoxide is not administered to the subject at any time in the claimed method. However, the claims have not specified a time during which the method elapses. Without the time limitation, one of ordinary skill would not understand when the negative limitation is not required anymore. For the purpose of examination, this is being interpreted as wherein the subject is not administered octreotide or diazoxide during steps (a) through (b).
Claims 6-9, 27-30, 42, 57-59, and 62-63 are rejected as being dependent on, and failing to cure the deficiencies of, rejected independent claim 1.
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, 6-7, 27-30, 42, and 57-59 are rejected under 35 U.S.C. 103 as being unpatentable over Prestrelski et al. (WO 2016196976 A1) in view of Lord et al. (2013 NPL- Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management).
Regarding claim 1, Prestrelski et al. discloses a method of treating congenital hyperinsulinism in a subject in need thereof ([0100] “Such embodiments may be suitable for treating patients having, for example, congenital hyperinsulinism”), comprising: a) parenterally administering to the subject (184 Fig 5 “intracutaneous delivery”) a first composition comprising glucagon, a glucagon analogue, or a salt form of either ([0012] “a composition comprising glucagon, a glucagon analogue, or a salt form of either”).
However, Prestrelski et al. fails to teach (b) administering to the subject a second composition comprising glucose, a glucose analogue, or a salt form of either, wherein the second composition is administered after (a), at a glucose infusion rate (GIR) of less than 7mg/(kg*min); wherein the subject is not administered octreotide or diazoxide.
Lord et al. teaches (b) administering to the subject a second composition comprising glucose, a glucose analogue, or a salt form of either, wherein the second composition is administered after (a), at a lower glucose infusion rate (GIR) (Lines 34-36 of page 6 column 1 “Glucagon can be used as a continuous intravenous infusion of 1 mg/day to lower glucose infusion rate requirements in infants awaiting surgery.”, Fig 2 “dextrose IV”); wherein the subject is not administered octreotide or diazoxide (Fig 2- “Stop Diazoxide, Initiate glucagon infusion”, and “Note that octreotide is not recommended as pre-operative treatment in neonates with HI due to high rate of treatment failure and risk of necrotizing enterocolitis.” As explained in the 112(b) rejection above, this is being interpreted as not being administered from steps (a) through (b)). It would have been obvious to one of ordinary skill in the art at the time of effective filing for the method of Prestrelski et al. to include the limitations as taught by Lord et al. “to lower glucose infusion rate requirements” (Lines 35-36 of page 6 column 1).
Modified Prestrelski et al. fails to explicitly teach the wherein the second composition is administered after (a), at a glucose infusion rate (GIR) of less than 7mg/(kg*min).
Lord et al. discloses hypoglycemia is identified by the requirement of high glucose infusion rates (Table 1 GIR > 10 mg/kg/min) and that the glucose infusion rates are able to be lowered by glucagon infusion (Lines 35-36 of page 6 column 1). The glucose infusion rate (GIR) is disclosed to be a result effective variable in that changing the GIR changes the blood glucose of the patient. Further, it appears that one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of modified Lord et al. to have a GIR within the claimed range as it involves adjusting the rate of infusion of a composition disclosed to require adjustment. Therefore, it would have been obvious to one having ordinary skill in the art at the time of the invention to modify the method of modified Lord et al. by making the second composition administered after (a), at a glucose infusion rate (GIR) of less than 7mg/(kg*min) as a matter of routine optimization since it has been held that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 6, modified Prestrelski et al. teaches the method of claim 1. Lord et al. further teaches wherein the second composition is intravenously administered to the subject (Fig 2 “dextrose IV”).
Regarding claim 7, modified Prestrelski et al. teaches the method of claim 1. Lord et al. further teaches wherein the subject undergoes treatment with a glucose injection at a second GIR that is greater than 7mg/(kg*min), prior to administration of the first composition (Table 1 GIR > 10 mg/kg/min, this is described as the GIR criteria for diagnosing hyperinsulinism and glucagon is used to lower this requirement).
Regarding claim 27, modified Prestrelski et al. teaches the method of claim 1. Prestrelski et al. further teaches a first composition is a single-phase solution comprising glucagon dissolved in an aprotic polar solvent ([0015] “In particular instances, the glucagon, glucagon analogue, or a salt form of either thereof, can be fully solubilized in an aprotic polar solvent.”).
Regarding claim 28, modified Prestrelski et al. discloses the method of claim 27. Prestrelski et al. further teaches wherein the first composition further comprises an ionization stabilizing excipient ([0015] “the therapeutic agent in an aprotic polar solvent system containing a specified concentration of at least one ionization stabilizing excipient.”), wherein (i) the glucagon, glucagon analogue, or salt thereof is dissolved in the aprotic polar solvent in an amount from about 0.1 mg/mL up to the solubility limit of the glucagon, glucagon analogue, or salt thereof ([0019] Certain embodiments are directed to a formulation of a therapeutic agent comprising a therapeutic agent at a concentration of at least, at most, or about 0.1, 1, 10, 50, or 100 mg/mL to 150, 200, 300, 400, or 500 mg/ml or up to the solubility limit of the therapeutic agent”), and (ii) the ionization 3stabilizing excipient is dissolved in the aprotic polar solvent in an amount to stabilize the ionization of the glucagon peptide or salt thereof ([0016] “In certain aspects a therapeutic agent is directly dissolved (e.g. a powder as received from a commercial manufacturer or supplier) along with an effective amount of an ionization stabilizing excipient for establishing an appropriate ionization of the therapeutic agent in the aprotic polar solvent system.”).
Regarding claim 29, modified Prestrelski et al. teaches the method of claim 28. Prestrelski et al. further teaches wherein the ionization stabilizing excipient is at a concentration of 0.1 mM to less than 100 mM ([0019] “In certain aspects the ionization stabilizing excipient concentration is between 0.1 mM to 100 mM.”).
Regarding claim 30, modified Prestrelski et al. teaches the method of claim 29. Prestrelski et al. further teaches wherein the ionization stabilizing excipient is a mineral acid ([0019] “the ionization stabilizing excipient may be a suitable mineral acid”).
Regarding claim 42, modified Prestrelski et al. teaches the method of claim 27. Prestrelski et al. further teaches wherein the first composition comprises at least 80 wt.% of the aprotic polar solvent, 3 to 7 wt. % of a carbohydrate, 0.001 to 0.1 wt. % of an amphoteric molecule, and 0 wt. % to less than 0.1 wt. % of an acid ([0021] “The composition can include at least 80 wt.% of the aprotic polar solvent, 3 to 7 wt. % of the carbohydrate, 0.001 to 0.1 wt. % of the amphoteric molecule, and 0 wt. % to less than 0.1 wt. % of the acid.”).
Regarding claim 57, modified Prestrelski et al. teaches the method of claim 1. Prestrelski et al. further teaches wherein the subject is human ([0038] “In particular aspects, the patient is a human.”).
However, Prestrelski et al. is silent to the age of the patient.
Lord et al. teaches the patient is less than 20 years old (Fig 2, “neonates”, a neonate is an infant less than 4 weeks old). It would have been obvious to one of ordinary skill in the art at the time of effective filing for the method of modified Prestrelski et al. to include the patient being a neonate as taught by Lord et al. to treat neonatal hypoglycemia because “Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children, which if unrecognized may lead to development delays and permanent neurologic damage.” (Introduction, Lines 1-4 of page 1 column 1).
Regarding claim 58, modified Prestrelski et al. teaches the method of claim 57. Lord et al. further teaches wherein the human is less than 10 years old, less than 5 years old, or within 0 to 3 years old (Fig 2, “neonates”, a neonate is an infant less than 4 weeks old).
Regarding claim 59, modified Prestrelski et al. teaches the method of claim 58. Lord et al. further teaches wherein the human is within 0 to 12 months old (Fig 2, “neonates”, a neonate is an infant less than 4 weeks old).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Prestrelski et al. (WO 2016196976 A1) in view of Lord et al. (2013 NPL- Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management), and Rule (WO 2011/031351 A1).
Regarding claim 8, modified Prestrelski et al. teaches the method of claim 7.
However, modified Prestrelski et al. is silent to wherein the glucose injection is administered through a peripherally inserted central catheter.
Rule teaches glucose injection is administered through a peripherally inserted central catheter ([0283] “Tight Glycemic Control (TGC) can include […] (2) determination of substances that tend to increase glucose levels (e.g., sugars such as dextrose) […] and/or (3) responsive delivery of one or more of such substances” , [0311] “delivery of some or all TGC-related medicaments through a common IV line (e.g., a proximal port of a central venous catheter or a lumen of a peripherally inserted central catheter)”). It would have been obvious to one of ordinary skill in the art at the time of effective filing for the glucose injection to be administered through a peripherally inserted central catheter as taught by Rule so there is “increased compliance with a treatment dosing protocol, reduction in treatment dosing errors, time savings for healthcare providers, and greater IV access efficiency by delivery of some or all TGC-related medicaments through a common IV line” [0311].
Claims 9 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Prestrelski et al. (WO 2016196976 A1) in view of Lord et al. (2013 NPL- Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management), and Callicoat et al. (US 2013/0297222 A1).
Regarding claim 9, modified Prestrelski et al. teaches the method of claim 1. Lord et al. further teaches wherein the second composition is a composition of d-glucose (Lines 34-36 of page 6 column 1 “Glucagon can be used as a continuous intravenous infusion of 1 mg/day to lower glucose infusion rate requirements in infants awaiting surgery.”, Fig 2 “dextrose IV).
However, modified Prestrelski et al. fails to teach an aqueous composition comprising 5 w/w % to 60 w/w % d-glucose.
Callicoat et al. teaches a glucose solution is an aqueous composition comprising 5 w/w % to 60 w/w % d-glucose ([00253] “the analyte (or a suitable compound related to the analyte) dissolved in water or saline. For example, if the analyte is glucose, the source 2782 may comprise a bag of dextrose solution (e.g., Dextrose or Dextrose 50%).”). It would have been obvious to one of ordinary skill in the art at the time of effective filing for the second composition of modified Prestrelski et al. to comprise 50 w/w % d- glucose as taught by Callicoat et al. as it is a composition capable of maintaining glycemic control [0249]. One of ordinary skill would be capable of determining which concentration of dextrose would be ideal for treating hypoglycemia in a patient.
Regarding claim 62, modified Prestrelski et al. teaches the method of claim 9. Lord et al. further teaches wherein the second composition comprises d-glucose (Fig 2 “dextrose IV”).
However, modified Prestrelski et al. is silent to the d-glucose is 50 w/w % d-glucose.
Callicoat et al. further teaches wherein the second composition comprises 50 w/w % d- glucose ([00253] “(e.g., Dextrose or Dextrose 50%).”). It would have been obvious to one of ordinary skill in the art at the time of effective filing for the second composition of modified Prestrelski et al. to comprise 50 w/w % d- glucose as taught by Callicoat et al. as it is a composition capable of maintaining glycemic control [0249]. One of ordinary skill would be capable of determining which concentration of dextrose would be ideal for treating hypoglycemia in a patient.
Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Prestrelski et al. (WO 2016196976 A1) in view of Lord et al. (2013 NPL- Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management), and Joseph et al. (US 2018/0243380 A1).
Regarding claim 63, modified Prestrelski et al. teaches the method of claim 9. Lord et al. further teaches wherein the second composition comprises d-glucose (Fig 2 “dextrose IV”).
However, modified Prestrelski et al. is silent to the d-glucose is 10 w/w % d-glucose.
Joseph et al. teaches a composition comprises 10 w/w % d- glucose ([0157] “10% dextrose infusion.”). It would have been obvious to one of ordinary skill in the art at the time of effective filing for the second composition of modified Prestrelski et al. to comprise 10 w/w % d- glucose as taught by Joseph et al. as it is a composition capable of establishing euglycemia [0157]. One of ordinary skill would be capable of determining which concentration of dextrose would be ideal for treating hypoglycemia in a patient.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/A.E.V./Examiner, Art Unit 3783
/COURTNEY FREDRICKSON/Primary Examiner, Art Unit 3783
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