DETAILED ACTION
Examiner acknowledges receipt of the reply filed 7/13/2026, in response to the non-final office action mailed 4/14/2026.
Claims 1, 13, 14, and 32-40 are pending. Claim 10 has been cancelled.
Claims 1, 13, 14, and 32-40 are being examined on the merits in this office 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 Arguments
Applicant's arguments filed 7/13/2026 have been fully considered but they are not persuasive. An action on the merits is presented below.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Claim Rejections - 35 USC § 103
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.
Claims 1, 13, 14, 32, and 35-40 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Stoffers et al. (U.S. 2008/0269130 - previously cited), as evidenced by Green et al (J Endocrinol 185:307-317 (2005)), in view of Gurman et al (Expert Rev Med Devices 11:205-223 (Jan 2014)- previously cited) and Makwana et al (Int’l J Pharma Invest 1: 200-206 (2011)- previously cited). The rejection is maintained from the office action mailed 4/14/2026, but has been amended to reflect claims filed 7/13/2026.
Stoffers et al. teach methods of treating and ameliorating post-prandial hypoglycemia [hyperinsulinemic hypoglycemia], comprising administering antagonist of the GLP-1 receptor (abstract, paras. [0005], [0027], [0044]-[0054], [0115]-[0123], [0137]). GLP-1 receptor antagonist include exendin (9-39) (e.g., paras. [0035]-[0037], [0050], [0064]-[0081]). Stoffers et al. teach that the GLP-1 receptor antagonist can be administered via subcutaneous administration (e.g., claim 13, paras. [0100]-[0108], [0141]). Stoffers et al. further teach that post-prandial hypoglycemia can also be caused by gastric-bypass surgery or Nissen fundoplication (paras. [0005], [0050]-[0055]). Stoffers et al. teach compositions comprising the GLP-1R antagonist (e.g., paras. [0100]-[0116]).
Stoffers et al. do not expressly teach that the composition is administered in a volume of 0.25-2 mL.
Gurman et al is a review article discussing the advantages of prefilled devices for parenteral applications (abstract). Parenteral delivery represents one of the most
important administration routes because many conditions requiring this route are acute and often times life-threatening. Parenteral delivery involves the administration through subcutaneous (sc.) route, often providing high bioavailability and rapid onset of action, a prerequisite for emergency situations where the parenteral route is the preferred (and sometimes the only alternative) route of rapid administration. The sc. route refers to the introduction of the drug into the tissue lying underneath the dermis and epidermis that constitutes the skin. The sc. route is the preferred route for at home injection, is adapted for short- and long-term therapies and compared with other parenteral routes, improves the quality of life (p. 205). Prefilled devices allow for accuracy of treatment, sterility, convenience, improved safety, and patient compliance (pp. 205-206 and 219-222. Gurman et al discusses commercially available prefilled devices (Table 1), and various dose volumes. Gurman et al further teach that prefilled device designs allow for dose adjustments (pp. 209 and 222).
Makwana et al is another review article teaching the advantages of prefilled devices – including convenience, affordability, accuracy, sterility, and safety (pp. 200-205). Prefilled devices can accommodate volumes typically ranging from 0.25 to 5 ml (p. 200).
It would have been obvious to one of ordinary skill in the art to subcutaneously administer a composition comprising exendin (9-39) to a patient for treating hyperinsulinemic hypoglycemia, wherein the composition was administered in a volume of 0.25 mL to 2 mL. Stoffers et al. explicitly taught methods of treating and ameliorating hyperinsulinemic hypoglycemia, as well as routes of administration (subcutaneous) (paras. [0106]-[0109], claim 13). Gurman and Makwana taught prefilled devices that allow for drug delivery via subcutaneous administration (volume range of 0.25 to 5 ml). The skilled artisan would have had a reasonable expectation of success because prefilled devices are increasingly being adopted due to their increasingly safe and easy utilization by patients, portability, accuracy of dose and quick delivery, which leads to increased patient compliance. Gurman further taught that prefilled device designs allow for dose/volume adjustments (pp. 209 and 222).
The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. In this case, Stoffers et al taught a method for treating hyperinsulinemic hypoglycemia in a subject comprising subcutaneous administration of a composition comprising a therapeutically effective amount of exendin(9-39). Gurman and Makwana taught devices for subcutaneous delivery of therapeutic agents, e.g., a composition comprising exendin(9-39), as well as the claimed volumes.
Furthermore, it would have been obvious to try subcutaneous as a route of administration of exendin(9-39).
It has been held that under KSR that “obvious to try” may be an appropriate test under 103. The Supreme Court stated in KSR, When there is motivation “to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR Int’l Co. v. Teleflex Inc., 127 S. Ct. 1727,_,82 USPQ2d 1385, 1397 (2007). Stoffers et al. explicitly taught methods of treating and ameliorating hyperinsulinemic hypoglycemia, as well as routes of administration (subcutaneous) (paras. [0104]-[0109], claim 13). Specifically, claim 13 recites a finite number of six (6) routes of administration: intravenous, parenteral, oral, inhalant, intraperitoneal, and subcutaneous.
The skilled artisan would have had reason to try subcutaneous administration with the reasonable expectation that at least one would be successful especially in light of the fact that the art teaches subcutaneous administration of exendin(9-39) for the same purpose as instantly claimed, treating hyperinsulinemic hypoglycemia. Thus, use of subcutaneous administration of exendin(9-39) for treating hyperinsulinemic hypoglycemia is “the product not of innovation but of ordinary skill and common sense,” leading to the conclusion that invention is not patentable as it would have been obvious.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). It is well-within the ordinary skill in the art to combine known components in known arrangements to obtain a known and expected result having a known and art-recognized utility. In addition, as evidenced by Green et al, subcutaneous administration of Ex(9–39) was known in the prior art, and Ex(9–39) was known to retain functional activity. Green et al disclose once daily subcutaneous injections (1700 h) of Ex(9–39) (25 nmol/kg in saline) over an 11-day period (p. 310). Green et al teach that subcutaneous administration of Ex(9–39) effectively blocked GLP-1 activity (e.g., Fig 1, pp. 310-315, Fig 1). Thus, it was well-within the ordinary skill in the art to administer exendin(9-39) by subcutaneous administration, with the expectation that exendin(9-39) would function in the manner as expected, e.g., treating hyperinsulinemic hypoglycemia. Gurman and Makwana taught devices for subcutaneous delivery of therapeutic agents, e.g., a composition comprising exendin(9-39), as well as the claimed volumes.
As noted, Stoffers et al. teach methods of treating and ameliorating post-prandial hypoglycemia [hyperinsulinemic hypoglycemia], comprising administering antagonist of the GLP-1 receptor, e.g., exendin (9-39), via subcutaneous administration (e.g., abstract, claim 13, paras. [0005], [0027], [0035]-[0037], [0044]-[0054], [0064]-[0081], [100]-[0108], [0115]-[0123], [0137], [0141]). Gurman and Makwana further taught prefilled devices [and volumes] that allow for drug delivery via subcutaneous administration. While Stoffers does not explicitly teach “wherein administration of the composition results in a steady state plasma exendin(9-39) concentration of at least 100 ng/mL as measured by liquid chromatograph-mass spectrometry”, the combined references perform the same steps [subcutaneous administration of a therapeutically effective amount of exendin(9-39) to the same patient population (patient with hyperinsulinemic hypoglycemia)]. As evidenced by Green et al, subcutaneous administration of Ex(9–39) was known in the prior art, and Ex(9–39) was known to retain functional activity [e.g., maintain steady state plasma exendin(9-39) concentration]. Because the method steps are the same, Stoffers et al. inherently teach the same effect of steady state plasma exendin(9-39) concentration as in the current claims. The cited references therefore render obvious the claimed steady state plasma exendin(9-39) concentration of at least 100 ng/mL as instantly claimed.
Accordingly, claim 1 is rendered obvious.
Regarding claims 13, 14, and 32, the optimization of result effect parameters (dosing regimen) is obvious as being within the skill of the artisan. The optimization of known effective amounts of known active agents to be administered, is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980). It is also noted that “[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 claims 35 and 36, Stoffers et al. teach that hyperinsulinemic hypoglycemia can be congenital, or acquired by gastric bypass surgery or Nissen fundoplication [gastrointestinal surgery] (abstract, paras. [0004]-[0010], [0027]-[0032], [0050]-[0054]). Regarding claim 37, Stoffers et al teach that the compositions can include saline [reads on isotonic solution] (paras. [0107]-[0108], [0158]). Regarding claim 38, Gurman et al discusses pen injectors for subcutaneous administration (e.g., pp. 206-215, 219-221, Table 1). Regarding claim 39, Stoffers et al teach that the compositions can include a buffer or preservative (paras. [0107]-[0109)). Regarding claim 40, Gurman et al discusses dual chamber devices that allow for drug and a lyophilized form and reconstitution of the powder drug prior to administration (pp. 207, 210, 219-222).
Claims 1, 13, 14, 32, and 35-40 are obvious in view of the teachings of the cited references.
Pursuant to MPEP 2121(I), when the reference relied on expressly anticipates or makes obvious all the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). Moreover, MPEP 2121(III) states that a prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006). MPEP 716.07 states that since in a patent it is presumed that a process if used by one skilled in the art will produce the product or result described therein, such presumption is not overcome by a mere showing that it is possible to operate within the disclosure without obtaining the alleged product. In re Weber, 405 F.2d 1403, 160 USPQ 549 (CCPA 1969).
Response to Arguments
Applicant traversed the rejection at pp. 4-6 of the reply filed 7/13/2026. Applicant asserts that the combined references do not teach or suggest that the composition “results in a steady state plasma exendin(9-39) of at least 100 ng/ml as measured by liquid chromatograph-mass spectrometry” (reply at p. 5). Applicant asserts “surprising results” in that subcutaneous administration resulted in a Cmax that was lower than observed from IV administration, however clinical efficacy of subcutaneous doses was equivalent to the efficacy that was achieved by continuous IV infusion of larger quantities of exendin(9-39) (reply at p. 5). Applicant asserts that the alleged unexpected and surprising results achieved by the claimed method are not suggested by the cited references, either alone or in combination. Applicant asserts that the instant claims are nonobvious over the combination of cited references (reply at p. 6).
Examiner has reviewed and considered applicants arguments, but is not persuaded.
As acknowledged by applicant, the “unexpected and surprising results [are] achieved by the claimed method”. The claimed method of subcutaneously administering a therapeutically effective amount of exendin(9-39) to a patient with hyperinsulinemic hypoglycemia is taught by Stoffers et al. Gurman and Makwana further taught prefilled devices [and volumes] that allow for drug delivery via subcutaneous administration. As evidenced by Green et al, subcutaneous administration of Ex(9–39) was known in the prior art, and Ex(9–39) was known to retain functional activity. Thus, the prior art taught the same composition, dosage, route of administration, and patient population as instantly claimed. The limitation merely recites a biological effect - “steady state plasma exendin(9-39) concentration” resulting from subcutaneous administration of the exendin(9-39). Because the prior art teaches the same method of treatment, any biological effects that necessarily result from practicing that method are inherent characteristics of the prior art method. The discovery or recognition of previously unappreciated biological mechanisms or properties resulting from an otherwise obvious method does not render the method patentable. See MPEP §2112. Furthermore, where the claimed and prior art methods are the same or substantially identical, the Office can reasonably require applicant to demonstrate that the prior art method does not inherently possesses the recited characteristics. See In re Best, 562 F.2d 1252, 1255 (CCPA 1977).
To the extent the recited physiological outcomes necessarily result from practicing the obvious treatment method, such outcomes constitute inherent characteristics of the prior art method and do not patently distinguish the instant claims.
Applicant has not provided persuasive evidence demonstrating that practicing the prior art method would fail to produce the recited biological effects.
The rejection is maintained for at least these reasons and those previously made of record.
Claim(s) 1, 10, 13, 14, and 32-40 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Stoffers et al. (U.S. 2008/0269130 - previously cited), as evidenced by Green et al (J Endocrinol 185:307-317 (2005)), Gurman et al (Expert Rev Med Devices 11:205-223 (Jan 2014)- previously cited) and Makwana et al (Int’l J Pharma Invest 1: 200-206 (2011)- previously cited), as applied to claims 1, 13, 14, 32, and 35-40 above, and further in view Franco et al. (Obes. Surg. 21:1458–1468 (2011)- previously cited). The rejection is maintained from the office action mailed 4/14/2026, but has been amended to reflect claims filed 7/13/2026.
The teachings of Stoffers et al., Green et al, Gurman and Makwana are set forth above. Stoffers et al. taught that post-prandial hypoglycemia can also be caused by gastric-bypass surgery or Nissen fundoplication (paras. [0005], [0050]-[0055]).
However, the references do not explicitly teach treatment of patients that have had other forms of bariatric or gastrointestinal surgeries.
Franco et al. is a review article discussing the advantages and disadvantages of three gastrointestinal surgeries: gastrectomy, Roux-en-Y gastric bypass and adjustable gastric banding (abstract; p. 159-146). Laparoscopic Roux-en-Y gastric bypass is one of the most commonly performed procedures for obese patients. Id.
It would have been obvious to the skilled artisan that a patient who has undergone a bariatric surgery or gastrointestinal surgery and developed hyperinsulinemic hypoglycemia would be a suitable candidate for treatment with exendin(9-39), as taught by Stoffers et al. The skilled artisan would have recognized that patients that have undergone bariatric and gastrointestinal procedures of sleeve Roux-en-Y gastric bypass, gastrectomy, and adjustable gastric banding could also be candidates for treatment with exendin(9-39). Claims 33 and 34 are deemed to be obvious.
Claims 1, 13, 14, and 32-40 are obvious in view of the teachings of the cited references.
Response to Arguments
Applicant traversed the rejection at p. 6 of the reply filed 7/13/2026. Applicant asserts that “Franco does not provide any information negating the reasons for nonobviousness of currently amended claim 1, or any of the dependent claims over Stoffers, Green, Gurman, and Makwana” and the instant claims are non-obvious over the cited references.
Examiner has reviewed and considered applicants arguments, but is not persuaded.
Examiner refers applicant to the above rebuttal arguments which also apply to the instant rejection and are incorporated herein.
Relevant Art Not Relied Upon
Xuan et al (Peptides 46:172-179 (2013)- previously cited) disclose in vitro bioactivity and in vivo pharmacokinetic profiles following subcutaneous administration of exenatide in rats (abstract, pp. 174-178). Xuan et al further disclose that exenatide is currently available in the market (Byetta) as twice-daily subcutaneous injection (5 or 10 µg/day) (p. 172)- e.g., before 2013. Exenatide is 39 amino acids in length. Id.
Examiner acknowledges that exenatide is longer than the claimed Ex(9-39), which is a truncated version of exenatide. However, Xuan et al established that subcutaneous administration of a functional peptide with overlapping sequence identity (amino acid positions 9-39) was known in the prior art. Thus, subcutaneous administration of the claimed Ex(9-39) would have had a reasonable expectation of success.
Grieve et al (Br J Pharamacol 157:1340-1351 (2009)- previously cited) disclose that exendin-4(1–39), shares 50% structural homology with GLP-1, has also been found to be a potent GLP-1R agonist, binding with comparable affinity to GLP-1 (p. 1342). Table 1 discloses that exenatide and exenatide-LAR are administered by subcutaneous administration. Grieve et al teach that Exendin(9-39) is an antagonist of GLP-1R (p. 1344).
Examiner acknowledges that exenatide is longer than the claimed Ex(9-39), which is a truncated version of exenatide/exendin-4(1-39). However, Grieve et al established that subcutaneous administration of a functional peptide with overlapping sequence identity (amino acid positions 9-39) was known in the prior art. Thus, subcutaneous administration of the claimed Ex(9-39) would have had a reasonable expectation of success.
Berteau et al (Patient Preference and Adherence 4:379-388 (2010)- previously cited) is an article discussing disposable auto injector pens for subcutaneous self-injection by patients. The autoinjector administered either 0.2 mL or 1 mL volume fluid (abstract). This study indicated that the autoinjector used by the subject was similar to a syringe used by a nurse in terms of performance and safety in administering the injections, and better in terms of pain, overall acceptance, and preference. Id.
Conclusion
No claims are allowed. Claims 1, 13, 14, and 32-40 are pending and are rejected.
THIS ACTION IS MADE FINAL. 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 KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/ Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654
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