Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections 35 USC 112(A)
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 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
While the claims are enabled for reducing the risk of hyperinsulinemic hypoglycemia, they are not enables for preventing it in all subjects. Claims 40-48 are rejected under 35 U.S.C. 112, first paragraph, because the specification does not reasonably provide enablement for prevention of hyperinsulinemic hypoglycemia using exendin(9-39). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to enable the invention commensurate in scope with this claim.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (reversing the PTO's determination that claims directed to methods for detection of hepatitis B surface antigens did not satisfy the enablement requirement). In Wands, the court noted that there was no disagreement as to the facts, but merely a disagreement as to the interpretation of the data and the conclusion to be made from the facts. In re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-07. The Court held that the specification was enabling with respect to the claims at issue and found that "there was considerable direction and guidance" in the specification; there was "a high level of skill in the art at the time the application was filed;" and "all of the methods needed to practice the invention were well known." 858 F.2d at 740, 8 USPQ2d at 1406. After considering all the factors related to the enablement issue, the court concluded that "it would not require undue experimentation to obtain antibodies needed to practice the claimed invention." Id., 8 USPQ2d at 1407.
(1) The nature of the invention and (5) The breadth of the claims:
The invention is drawn to a method of preventing hyperinsulinemic hypoglycemia; however, the experimental results yield no definitive evidence that it can be prevented by the administration of exendin(9-39) in all cases.
(2) The state of the prior art:
In regards to “preventing hyperinsulinemic hypoglycemia”, it is known in the art that hyperinsulinemic hypoglycemia depends on a variety of factors, including congenital factors. This condition is known to be caused by mutations in 16 different key genes, that regulate insulin secretion from beta-cells of the pancreas (Sabi et al. 2024). Sabi also teaches that Hyperinsulinemic Hypoglycemia (HH) in infants and newborn babies in the postnatal period is considered a complex of disorders related to dysregulated insulin secretion that occurs when plasma glucose levels decrease, leading cells to inappropriate insulin secretion (abstract).
Thus, it is well known that hyperinsulinemic hypoglycemia is not an altogether preventable condition, as it is caused by a variety of genetic and other factors.
(3) The relative skill of those in the art:
The relative skill of those in the art is high.
(4) The predictability or unpredictability of the art:
Applicant’s claims are based on predicting subjects that would be susceptible to hyperinsulinemic hypoglycemia to make it preventable in all cases. Thus, the predictability in the art is low.
The claims do not identify the patient population in which this can be prevented, and have only provided data showing protection against hyperinsulinemic hypoglycemia (Table 7; Cohort of 32 healthy subjects), therefore, the claims imply that anyone can be prevented from having hyperinsulinemic hypoglycemia. However, the examples have not provided any evidence of prevention, but instead evidence of treatment.
(6) The amount of direction or guidance presented and (7) The presence or absence of working examples:
As described supra, the state of the art recognizes that those susceptible to hyperinsulinemic hypoglycemia are subject to a variety of factors which cause it.
The specification has not provided clear guidance as to how to determine the patient population that would be susceptible, and has not shown that it can prevent this condition in the entirety of the population, especially those that have genetic causes of hyperinsulinemic hypoglycemia.
(8) The quantity of experimentation necessary:
Because it is uncertain to predict the patient population susceptible to hyperinsulinemic hypoglycemia, as well as what time and to what population the compound should be administered to prevent each, one of ordinary skill in the art would be burdened with undue “painstaking experimentation study” to determine how to use the claimed compound to prevent hyperinsulinemic hypoglycemia where it has a genetic cause.
Please note that the term “prevent” in an absolute definition which means to stop from occurring and, thus, requires a higher standard for enablement than does “therapeutic” or “treat” or “alleviate”, especially since it is notoriously well accepted in the medical art that the vast majority of afflictions/disorders suffered by mankind cannot be totally prevented with current therapies (other than certain vaccination regimes, genetic engineering), including preventing hyperinsulinemic hypoglycemia.
Non-Statutory 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.
Claims 29-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,020,484. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘484 are the following:
1. A liquid pharmaceutical formulation comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of above 5.1 to 6, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof does not exhibit detectable aggregation in the formulation, and wherein the liquid pharmaceutical formulation, when administered to a human subject, has an improved pharmacokinetic profile as compared to a composition comprising the same dose of exendin (9-39) or a pharmaceutical acceptable salt thereof formulated in 0.9% normal saline.
2. The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises an acetate buffer or a citrate buffer.
3. The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate or sodium citrate.
4. The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate or sodium citrate at a concentration from about 5 mM to about 30 mM.
5. The liquid pharmaceutical formulation of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.
6. The liquid pharmaceutical formulation of claim 1, wherein the buffer has a pH in the range of 5.2 to 5.8.
7. The liquid pharmaceutical formulation of claim 6, wherein the pH is about 5.5.
8. The liquid pharmaceutical formulation of claim 1, wherein the tonicity modifier comprises mannitol, dextrose, glycerin, lactose, sucrose, or trehalose.
9. The liquid pharmaceutical formulation of claim 8, wherein the tonicity modifier comprises mannitol.
10. 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.
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.
12. The liquid pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable salt of exendin (9-39) is exendin (9-39) acetate or exendin (9-39) trifluoroacetate.
13. 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.
14. The liquid pharmaceutical formulation of claim 13, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of at least 15 mg/ml.
15. The liquid pharmaceutical formulation of claim 13, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 30 mg/ml.
16. The liquid pharmaceutical formulation of claim 13, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 60 mg/ml.
17. The liquid pharmaceutical composition of claim 1, formulated for subcutaneous administration.
18. The liquid pharmaceutical formulation of claim 1, wherein the liquid pharmaceutical formulation, when administered to a human subject, exhibits a higher Cmax for exendin (9-39) than a composition comprising the same dose of exendin (9-39) or a pharmaceutical acceptable salt thereof formulated in 0.9% normal saline.
19. The liquid pharmaceutical formulation of claim 1, wherein the liquid pharmaceutical formulation, when administered to a human subject, exhibits a higher 12-hour AUC for exendin (9-39) than a composition comprising the same dose of exendin (9-39) or a pharmaceutical acceptable salt thereof formulated in 0.9% normal saline.
20. The liquid pharmaceutical formulation of claim 1, wherein the liquid pharmaceutical formulation, when administered to a human subject, exhibits a higher trough plasma concentration for exendin (9-39) than a composition comprising the same dose of exendin (9-39) or a pharmaceutical acceptable salt thereof formulated in 0.9% normal saline.
21. A method of treating or preventing hyperinsulinemic hypoglycemia in a subject, comprising administering to the subject the liquid pharmaceutical formulation of claim 1.
22. The method of claim 21, wherein the subject has previously had an upper-gastrointestinal procedure.
23. The method of claim 22, wherein the subject has previously had a bariatric procedure.
24. 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).
25. The method 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, 45 mg, or 90 mg QD.
26. The method 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 15 mg, 30 mg, or 45 mg twice daily (BID).
27. The liquid pharmaceutical formulation of claim 13, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 45 mg/ml.
28. The liquid pharmaceutical formulation of claim 13, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof is at a concentration of about 90 mg/ml.
29. The method of claim 21, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a daily dosage of about 30 mg, 45 mg, or 90 mg.
30. The method of claim 29, wherein the method comprises subcutaneously administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) once per day (QD) or twice per day (BID).
Claim 1 of ‘484 meets the limitations of claims 29-31, 39, by teaching a pharmaceutical composition comprising exendin (9-39) or a pharmaceutically acceptable salt thereof with a tonicity modifier in a physiologically acceptable buffer having a pH in the range of above 5.1 to 6, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof does not exhibit detectable aggregation in the formulation. Instant claims 32 and 33 are met by claims 2 and 3 of ‘484, which teach the same buffer formulations. Instant claims 34 and 35-38 are met because claims 8-9 of ‘484 teach mannitol, dextrose, glycerin, lactose, sucrose, or trehalose. Instant claim 35 is met is met by claim 28 teaches subcutaneous injection, rendering this obvious, as well as claims 40-48, which are drawn to methods of treating hyperinsulinemia via various methods of administration and overlapping disorders of claims 21-30. As such, claims 1-30 of ‘484 render obvious the instant claims.
Claims 29-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 11,738,086. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-7 teach the following:
1. A method for treating hyperinsulinemic hypoglycemia (HH) in a subject, the method comprising administering to the subject a liquid pharmaceutical formulation comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of 5.1 to 6; wherein the liquid pharmaceutical formulation is formulated for oral, intravenous, buccal, rectal, parenteral, intraperitoneal, intradermal, intramuscular, subcutaneous, or inhalational administration; wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof does not exhibit detectable aggregation in the pharmaceutical liquid formulation; and wherein the liquid pharmaceutical formulation has an improved pharmacokinetic profile as compared to a composition comprising the same dose of exendin (9-39) or a pharmaceutical acceptable salt thereof formulated in 0.9% normal saline.
2. The method of claim 1, wherein the method comprises administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) at a daily dosage of about 30 mg to 90 mg.
3. The method of claim 2, wherein the method comprises administering to the subject the liquid pharmaceutical formulation comprising exendin (9-39) once per day (QD) or twice per day (BID).
4. 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).
5. The method 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 15 mg, 30 mg, or 45 mg twice daily (BID).
6. The method of claim 1, wherein the subject has previously had an upper-gastrointestinal procedure.
7. The method of claim 1, wherein the subject has previously had a bariatric procedure.
This renders obvious instant claims 29-31 and 40-48 by teaching the same pharmaceutical formulation in the same pH with the same tonicity and buffer formulations for treating the same hyperinsulinemia conditions.
Instant claims 33-39 are met because claims 8-18 teach the following:
8. The method of claim 1, wherein the physiologically acceptable buffer comprises an acetate buffer or a citrate buffer.
9. The method of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate or sodium citrate.
10. The method of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate or sodium citrate at a concentration from about 5 mM to about 30 mM.
11. The method of claim 1, wherein the physiologically acceptable buffer comprises sodium acetate at a concentration of about 10 mM.
12. The method of claim 1, wherein the physiologically acceptable buffer has a pH in the range of 5.2 to 5.8.
13. The method of claim 12, wherein the pH is about 5.5.
14. The method of claim 1, wherein the tonicity modifier comprises mannitol, dextrose, glycerin, lactose, sucrose, or trehalose.
15. The method of claim 14, wherein the tonicity modifier comprises mannitol.
16. The method of claim 14, wherein the tonicity modifier is present in an amount from about 20 mg/ml to about 60 mg/ml.
17. The method of claim 16, wherein the tonicity modifier is present in an amount that achieves an osmolality of 290 mOsm/kg.
18. The method of claim 1, wherein the pharmaceutically acceptable salt of exendin (9-39) is exendin (9-39) acetate or exendin (9-39) trifluoroacetate.
This meets the limitations of instant claims 35-39 by teaching the same buffers, routes of administration, tonicity agents, preservatives (mannitol) and surfactants. As such, the claims of 086 meet the limitations of the instant claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANETTE M LIEB whose telephone number is (571)270-3490. The examiner can normally be reached M-F 10-7.
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/JEANETTE M LIEB/Primary Examiner, Art Unit 1654