DETAILED ACTION
Examiner acknowledges receipt of the reply filed 11/03/2025, in response to the non-final office action mailed 7/15/2025.
Claims 1, 2, 4-8, 10, 12, 13, and 19-32 are pending and 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 .
Priority
The amendment filed 11/3/2025 has support to provisional Appl. 62/303983. Accordingly, the earliest filing date for the instant claims is deemed to be the filing date of provisional application 62/303983, filed 03/04/2016.
Response to Arguments
Applicant's arguments filed 11/03/2025 have been fully considered but they are not persuasive. An action on the merits is set forth herein.
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.
Maintained Rejection
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.
Claim(s) 1, 2, 4-8, 12, 13, and 22-33 remain/are rejected under 35 U.S.C. 103 as being unpatentable McLaughlin et al (U.S. 2018/0147261- 102a2 date 5/22/2015 of Prov Appl 62/165743- cited in IDS filed 6/7/2024. See also CON Prov Appl 62/326850, filed 4/29/2016- previously cited), in view of Seeley et al. (U.S. 2004/0116331- previously cited). This rejection is maintained from the office action mailed 7/15/2025, but has been amended to reflect claims filed 11/03/2025.
McLaughlin et al taught a method of treating hyperinsulinemic hypoglycemia comprising administering exendin(9-39) or pegylated exendin(9-39) in a dosage amount ranging from 20-50 mg, 20-40 mg, 2-10 mg, 2.5-10 mg, or 2.5-7.5 mg, depending upon the needs and physical attributes of the patient. In some embodiments, adult patients (60-100 kg or more) will receive therapeutic benefit from a single dose in the range of 10-75 mg, with some achieving full therapeutic effect with 20-40 mg e.g., (abstract, paras. [0005]-[0010], [0046]-[0050], [0085], claims 5, 10, 12-24). McLaughlin et al taught subcutaneous administration (claims 1, 23-24; paras. [0005], [0007]-[0033]). The reference explicitly taught PEGylated exendin(9-39) (e.g., paras. [0049]-[0050]). McLaughlin et al taught that the methods, formulations, and examples discussed are equally applicable to any GLP-1RAs having similar biochemical structure to exendin(9-39), including but not limited to other exendin analogues, pegylated versions, acylated versions, and amino acid variants thereof. (para. [0050]). McLaughlin et al taught that the patient has had bariatric surgery [Roux-en-Y gastric bypass, vertical sleeve gastrectomy], gastrointestinal surgery [Nissen Fundoplication], or congenital hyperinsulinemic hypoglycemia (e.g., paras. [0051]-[0057], [0063]). The exendin-4 derivative dose can be 15-45 mg (e.g., claim 16); administered once or twice a day e.g., paras. [0006], [0074], [0107], claims 12 and 16). The exendin-4 derivative is administered at least 60 minutes [reads on an hour] before a morning meal (e.g., claim 16; paras. [0007]-[0008], [0078]-[0082], [0100]).
Although McLaughlin et al. taught administration of exendin(9-39) or pegylated exendin(9-39), the reference does not explicitly teach administration of exendin(3-39), exendin(4-39), exendin(5-39), exendin(6-39), exendin(7-39), or exendin(8-39), or pegylated forms thereof.
Seeley et al. taught GLP-1 and GLP-1 receptor antagonists and methods of use (abstract). GLP-1 receptor antagonists include exendin (9-39) and exendin (3-39) through exendin (8-39), e.g., exendin (5-39) (para. [0043]). Thus, Seeley et al. taught that all of these exendin-4 derivatives are GLP-1 receptor antagonists.
It would have been obvious to the skilled artisan to administer exendin (3-39), exendin(4-39), exendin(5-39), exendin(6-39), exendin(7-39), or exendin(8-39) [or pegylated forms thereof] to a patient with hyperinsulinemic hypoglycemia in order to treat the hyperinsulinemic hypoglycemia. The skilled artisan would have recognized that McLaughlin et al. taught that exendin (9-39) [a GLP-1 receptor antagonist] could be useful for such purposes. The artisan would have been motivated to use one of the recited exendin-4 derivatives because Seeley et al. explicitly taught that exendin-4 derivatives were all GLP-1 receptor antagonists. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”). The skilled artisan would have had a reasonable expectation of success in administering exendin (3-39), exendin(4-39), exendin(5-39), exendin(6-39), exendin(7-39), or exendin(8-39) [or pegylated forms thereof] in the claimed dose range to a patient with hyperinsulinemic hypoglycemia because McLaughlin et al. et al. taught administering GLP-1 antagonists to treat patients with hyperinsulinemic hypoglycemia. The skilled artisan would have recognized that exendin (3-39) through exendin (9-39) are all GLP-1 antagonists and functional equivalents. McLaughlin et al further taught the claimed dose range (e.g., 20-50 mg, paras. [0006]-[0010], [0085], claims 12, 14-16, 19, 21, 22).
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. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). In this case, the prior art taught that exendin (3-39) through exendin (9-39) are all exendin-4 derivatives, GLP-1 antagonists and functional equivalents that could be used to treat hyperinsulinemic hypoglycemia, so the motivation to substitute exendin (9-39) with exendin (3-39) through exendin (8-39) [or pegylated forms thereof] can be found in the common knowledge of the art and common sense of its skilled practitioners.
Additionally, it would have been obvious to one of ordinary skill in the art to combine the teachings of McLaughlin et al and Seeley et al because both references teach exendin-4 derivatives as GLP-1 antagonists. McLaughlin et al taught that GLP-1 antagonists could be used to treat hyperinsulinemic hypoglycemia using the claimed dose ranges. McLaughlin et al explicitly taught exendin(9-39) and pegylated exendin(9-39). Seeley et al taught that exendin(3-39) through exendin(9-39) were all GLP-1 antagonists, and therefore functional equivalents. One of ordinary skill in the art would be motivated to try with a reasonable expectation of success. 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.
The “problem” facing those in the art was available GLP-1 antagonists for treating hyperinsulinemic hypoglycemia. McLaughlin et al taught that the genus of GLP-1 antagonists could be used to treat hyperinsulinemic hypoglycemia. The reference further explicitly taught the species of exendin(9-39) and pegylated exendin(9-39) for treating hyperinsulinemic hypoglycemia. The prior art taught a limited number of GLP-1 antagonists. Seeley et al explicitly taught exendin(3-39) through exendin(9-39) – 7 peptides- were all exendin derivatives and GLP-1 antagonists. The skilled artisan would have had reason to try exendin(3-39) through exendin(8-39) with the reasonable expectation that at they would be successful. Administration of peptide of exendin(3-39) through exendin(9-39), or a pegylated form thereof at a dose of 20-50 mg, instead of exendin(9-39) for treating hyperinsulinemic hypoglycemia, as set forth in McLaughlin et al, is a “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.
Accordingly, claims 1 and 27-32 are rendered obvious.
Regarding claim 2, Seeley et al explicitly taught exendin(3-39) through exendin(9-39) – 7 peptides- were all exendin derivatives and GLP-1 antagonists The skilled artisan would have had reason to try exendin(5-39) with the reasonable expectation that the peptide would be successful. Regarding claim 4, McLaughlin et al teach subcutaneous administration (claims 1, 23-24; paras. [0005], [0007]-[0033], [0063], [0068]-[0069]). Regarding claims 5-8, McLaughlin et al teach that the patient has had bariatric surgery [Roux-en-Y gastric bypass, vertical sleeve gastrectomy], gastrointestinal surgery [Nissen Fundoplication], or congenital hyperinsulinemic hypoglycemia (e.g., paras. [0051]-[0057], [0063]). Regarding claim 10, the exendin-4 derivative dose can be 20-50 mg, 45 mg (e.g., claim 16, paras. [0006], [0072]-[0073], [0085]). Regarding claims 12 and 13, the exendin-4 derivative is administered once or twice a day e.g., paras. [0006], [0074], [0107], claims 12 and 16). Regarding claims 22 and 23, the exendin-4 derivative is administered at least 60 minutes [reads on an hour] before a morning meal (e.g., claim 16; paras. [0007]-[0008], [0078]-[0082], [0100]). Regarding claim 24, the exendin-4 derivative is in an isotonic solution (e.g., paras. [0096], [0103], [0109]-[0110]). Regarding claim 25, the exendin-4 derivative is administered using a pen injector (e.g., paras. [0102]-[0103], [0110], [0124]). Regarding claim 26, the exendin-4 derivative can be in a pharmaceutical composition further comprising an antimicrobial preservative, a tonicity adjusting agent, or a buffer (e.g., paras. [0005], [0012], [0069], [0083]-[0111]).
Claims 1, 2, 4-8, 12, 13, and 22-33 are obvious in view of the teachings of McLaughlin et al. and Seeley et al.
Response to Arguments
Applicant traversed the rejection in the reply filed 11/03/2025 at pp. 6-9. Applicant asserts that the cited references do not teach or suggest a method of treating hyperinsulinemic hypoglycemia comprising a dose of 10-75mg of a recited exendin-4 derivative (reply at p. 7). Applicant asserts that McLaughlin describes avexitide [also known as exendin(9-39)] for treating hyperinsulinemic hypoglycemia and list ranges of doses and frequencies as possibilities for dosing regimens, but does not suggest the claimed exendin-4 derivatives. Id.
Applicant asserts that Seeley is not remedying the alleged deficiency of McLaughlin (reply at p. 8). Applicant asserts that Seeley relates to the use of GLP-1 antagonists for their ability to produce a sedative or anxiolytic effect in a subject. Applicant further asserts that the reference focuses on weight-based dosing, not the claimed dose of 10-75 mg. Id.
Applicant asserts that the cited references do not direct the skilled artisan to the claimed method, reciting specific combinations of elements. Id. Applicant states: The offices rationale appears to require the person “pick and choose” a specific exendin-4 derivative is selected from the group of recited exendin-4 derivatives, administered at a dose of 10-75 mg. Applicant asserts that the cited references “do not direct the skilled artisan to make those specific selections”. Id. Applicant asserts that where the reference clearly presents a list of possibilities, anticipation or obviousness cannot be based on “picking and choosing” disparate elements to reconstruct the claimed invention, referring to In re Arkley, In re Baird, and In re Jones (reply at p. 8).
Examiner has reviewed and considered applicants arguments but is not persuaded.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant focuses on the term avexitide which is merely another name for the compound exendin(9-39). McLaughlin explicitly teaches administering exendin(9-39) [or pegylated exendin(9-390] to treat hyperinsulinemic hypoglycemia, as well as dosage amounts and routes of administration (e.g., paras. [0005]-[0010], [0046]-[0050], [0085], examples, claims 1, 5, 12, 16).
Contrary to applicant’s assertions, the Seeley reference is not limited to GLP-1 antagonists and sedative/anxiolytic effects, and weight-based dosing. Examiner reminds applicant that patents and applications are relevant as prior art for all they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). Seeley expressly teaches that GLP-1 receptor antagonists include exendin (9-39) and exendin (3-39) through exendin (8-39), e.g., exendin (5-39) (para. [0043]). Seeley et al. taught that all of these exendin-4 derivatives are GLP-1 receptor antagonists. Thus, the prior art taught that exendin (3-39) through exendin (9-39) are functional equivalents.
Regarding applicant’s assertions of “picking and choosing”, substituting one functional equivalent for another would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”). Additionally, there are only 7 peptides- again, all of which are functional equivalents- thus 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. This 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., 550 U.S. 398, 402 (2007). See also In re Fout, 675 F.2d 297, 301 (C.C.P.A. 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”).
Applicant’s reliance on In re Arkley, 455 F.2d 586, 587 (C.C.P.A. 1972) is misplaced. The case states although “[s]uch picking and choosing may be entirely proper in the making of a 103, obviousness rejection . . . it has no place in the making of a 102, anticipation rejection.” Arkley, 455 F.2d at 587-88. The instant rejection is a §103 obviousness rejection, not a §102 rejection. Examiner further notes that the instant rejection is distinguishable and based on a combination of references.
With regard to In re Baird and In re Jones, the cited references disclose specific species - not a genus - of functional equivalents, exendin(3-39), exendin(4-39), exendin(5-39), exendin(6-39), exendin(7-39), exendin(8-39), and exendin(9-39).
The rejection is maintained for at least the reasons set forth herein and those previously made of record. Please see the above rejection for specific details.
Claim(s) 1, 2, 4-8, 10, 12, 13, and 19-32 remain/are rejected under 35 U.S.C. 103 as being unpatentable over McLaughlin et al (U.S. 2018/0147261- 102a2 date 5/22/2015 of Prov Appl 62/165743- previously cited. See also CON Prov Appl 62/326850, filed 4/29/2016- previously cited) and Seeley et al. (U.S. 2004/0116331- previously cited), as applied to claims 1, 2, 4-8, 12, 13, and 22-32 above, and further in view of Veronese et al (Biodrugs 22: 315-329 (2008)- previously cited). This rejection is maintained from the office action mailed 7/15/2025, but has been amended to reflect claims filed 11/03/2025.
Although McLaughlin teaches pegylated exendin(9-39), the reference does not explicitly teach the limitations of instant claims 19-21.
Veronese et al is a review article discussing pegylation of biological therapies, including peptides and proteins, as well as methods of preparing pegylated conjugates (see Veronese et al generally). The term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency (abstract). Veronese et al teach conjugation of PEG at the N- or C- termini of peptides/proteins (e.g., pp. 317-320).
It would have been obvious to one of ordinary skill in the art to modify an exendin-4 derivative of McLaughlin with a PEG moiety at the N- or C- termini of the exendin-4 peptide. The skilled artisan would have recognized that McLaughlin taught pegylated exendin(9-39) and that Veronese et al taught methods of preparing/modifying peptides to obtain peptide-PEG conjugates. The skilled artisan would have had a reasonable expectation of success because Veronese et al explicitly taught methods of preparing peptides comprising a PEG moiety at the N- and/or C- termini. Accordingly, claims 19 and 20 are rendered obvious.
Regarding claim 21, Veronese et al teach that PEG group sizes include 5-40 kD (Table 2, pp. 320-321).
Accordingly, claims 1, 2, 4-8, 10, 12, 13, and 19-32 are obvious in view of the teachings of the cited references.
Response to Arguments
Applicant traversed the rejection in the reply filed 11/03/2025 at p 9. Applicant asserts that the cited references do not teach or suggest a method of treating hyperinsulinemic hypoglycemia comprising a dose of 10-75mg of a recited exendin-4 derivative (reply at p. 9). Applicant asserts that Veronese does not remedy the alleged deficiencies of references McLaughlin and Seeley. Id. Applicant asserts that Veronese “is cited for the purpose of describing pegylation of biological therapies”, and that the combination of cited references “fails to teach or suggest all limitations of claim 1”. Id.
Examiner has reviewed and considered applicants arguments but is not persuaded.
Examiner refers applicant to the above rebuttal arguments that pertain to this rejection as well. The rejection is maintained for at least the reasons set forth herein and those previously made of record. Please see the above rejection for specific details.
Claims 1, 2, 4, 5, 7, 8, 10, 12, 13, 22-24, and 26-32 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 Calabria et al (Diabetes 61:2585-2591 (2012)- previously cited), in view of Pai (Pharmacotherapy 32: 856–868 (2012)- previously cited) and Seeley et al. (U.S. 2004/0116331- previously cited). This rejection is maintained from the office action mailed 7/15/2025, but has been amended to reflect claims filed 11/03/2025.
Calabria is a journal article by named inventors of Stoffers et al. Specifically, inventors De Leon and Stanley of Stoffers et al are co-authors in the Calabria reference.
Stoffers et al. teach methods of treating and ameliorating congenital and neonatal hyperinsulinism and post-prandial hypoglycemia, comprising the step of administering an antagonist of the glucagon-like peptide-1 (GLP-1) receptor (abstract, paras.[0005], [027], [0044]-[0054], [0122]). GLP-1 receptor antagonists include exendin-4 and analogues thereof (paras. [0074]-[0077]). Stoffers et al. teach that the compounds can include modifications of water-soluble polymers such as polyethylene glycol [reads on pegylated] (para. [0114]). Exendin (9-39) was reduced to practice (Ex. 1-6). Example 6 teaches a 6 hour intravenous infusion of exendin-(9-39) at ascending doses every 120 min (100 pmol/kg/min for 120 min, then 300 pmol/kg/min for 120 min and then 500 pmol/kg/min for 120 min). Stoffers et al teach various dose amounts (paras. [0117]-[0121]).
Calabria et al disclose treatment of the same patient population and dosage regimen as disclosed in Example 6 of Stoffers et al. Subjects received an intravenous infusion of vehicle (0.9% NaCl) for 1 h followed by an intravenous infusion of exendin-(9-39) at 100 pmol/kg/min (0.02 mg/kg/h) for 2 h and then 300 pmol/kg/min (0.06 mg/kg/h) for 2 h, followed by 500 pmol/kg/min (0.1 mg/kg/h) for the last 2 h (p. 2586).
Pai teach that the average weight of an adult in the US is 81 kg (pp. 860-861, 866).
Per Stoffers et al, as evidenced by Calabria et al, using the average weight of adult (81 kg) administration of exendin(9-39) would equate to the following:
100 pmol/kg/min (0.02 mg/kg/h) for 2 h = 0.02 mg X 81 kg x 2 hr = 3.24 mg
300 pmol/kg/min (0.06 mg/kg/h) for 2 h = 0.06 mg x 81 kg x 2 hr = 9.72 mg
500 pmol/kg/min (0.1 mg/kg/h) for 2 h = 0.1 mg x 81 kg x 2 hr = 16.2 mg
This would provide a total dosage of 29.16 mg exendin(9-39).
The instant specification defines “hyperinsulinemic hypoglycemia" as “encompass[ing] the conditions dumping syndrome, nesideoblastosis, noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS), and/or post-prandial reactive hypoglycemia. Hyperinsulinemic hypoglycemia may result from a gastric or bariatric procedure (specification at para. [0031]). Stoffers is deemed to teach a method of treating hyperinsulinemic hypoglycemia comprising administration of exendin-4.
Although Stoffers et al. teach administration of exendin(9-39), the reference does not explicitly teach administration of exendin(3-39), exendin(4-39), exendin(5-39), exendin(6-39), exendin(7-39), or exendin(8-39), or pegylated forms thereof.
Seeley et al. teach GLP-1 and GLP-1 receptor antagonists and methods of use (abstract). GLP-1 receptor antagonists include exendin (9-39) and exendin (3-39) through exendin (8-39), e.g., exendin (5-39) (para. [0043]). Thus, Seeley et al. teach that all of these exendin-4 derivatives are GLP-1 receptor antagonists.
It would have been obvious to the skilled artisan to administer exendin (3-39), exendin(4-39), exendin(5-39), exendin(6-39), exendin(7-39), or exendin(8-39) [or pegylated forms thereof] to a patient with hyperinsulinemic hypoglycemia in order to treat the hyperinsulinemic hypoglycemia. The skilled artisan would have recognized that Stoffers et al. taught that exendin (9-39) [a GLP-1 receptor antagonist] could be useful for such purposes. The artisan would have been motivated to use one of the recited exendin-4 derivatives because Seeley et al. explicitly taught that exendin-4 derivatives were all GLP-1 receptor antagonists. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”). The skilled artisan would have had a reasonable expectation of success in administering exendin (3-39), exendin(4-39), exendin(5-39), exendin(6-39), exendin(7-39), or exendin(8-39) [or pegylated forms thereof] in the claimed dose range to a patient with hyperinsulinemic hypoglycemia because Stoffers et al. et al. taught administering GLP-1 antagonists to treat patients with hyperinsulinemic hypoglycemia. The skilled artisan would have recognized that exendin (3-39) through exendin (9-39) are all GLP-1 antagonists and functional equivalents. Stoffers et al teach various dose amounts (paras. [0117]-[0121]). As evidenced by Calabria and Pai, dosage amounts fell within the instant claim scope.
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. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). In this case, the prior art taught that exendin (3-39) through exendin (9-39) are all GLP-1 antagonists and functional equivalents that could be used to treat hyperinsulinemic hypoglycemia, so the motivation to substitute exendin (9-39) with exendin (3-39) through exendin (8-39) [or pegylated forms thereof] can be found in the common knowledge of the art and common sense of its skilled practitioners.
Additionally, it would have been obvious to one of ordinary skill in the art to combine the teachings of Stoffers et al and Seeley et al because both references teach exendin derivatives as GLP-1 antagonists. Stoffers et al taught that GLP-1 antagonists could be used to treat hyperinsulinemic hypoglycemia using the claimed dose ranges. Stoffers et al explicitly taught exendin(9-39) and pegylated form thereof. Seeley et al taught that exendin(3-39) through exendin(9-39) were all exendin-4 derivatives/GLP-1 antagonists, and therefore functional equivalents. One of ordinary skill in the art would be motivated to try with a reasonable expectation of success. 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.
The “problem” facing those in the art was available GLP-1 antagonists for treating hyperinsulinemic hypoglycemia. Stoffers et al taught that the genus of GLP-1 antagonists could be used to treat hyperinsulinemic hypoglycemia. The reference further explicitly taught the species of exendin(9-39) for treating hyperinsulinemic hypoglycemia. The prior art taught a limited number of GLP-1 antagonists. Seeley et al explicitly taught exendin(3-39) through exendin(9-39) – 7 peptides- were all exendin-4 derivatives and GLP-1 antagonists. The skilled artisan would have had reason to try exendin(3-39) through exendin(8-39) with the reasonable expectation that at they would be successful. Administration of a peptide of exendin(3-39) through exendin(9-39), or a pegylated form thereof, instead of exendin(9-39) for treating hyperinsulinemic hypoglycemia, as set forth in Stoffers et al, is a “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.
Accordingly, claims 1 and 27-32 are deemed to be obvious.
Regarding claim 2, Seeley et al explicitly taught exendin(3-39) through exendin(9-39) – 7 peptides- were all exendin derivatives and GLP-1 antagonists The skilled artisan would have had reason to try exendin(5-39) with the reasonable expectation that the peptide would be successful. Regarding claim 4, the exendin-4 derivative may be administered subcutaneously to the patient (e.g., Stoffers et al. at e.g., claim 13, paras. [0100]-[0106]). Regarding claims 5 and 7, Stoffers et al. teach that post-prandial hypoglycemia can also be caused by gastric bypass surgery for obesity [reads on bariatric surgery] (e.g., paras. [0005], [0050]-[0054]). Regarding claim 8, the patient can have congenital hyperinsulinemic hypoglycemia (e.g., abstract, claims 1-10; paras. [0007]-[0010]. [0026]-[0043]. Regarding claims 12, Stoffers et al. teach an infusion of the peptide (Ex. 6, para. [0120]).
Regarding claim 10, Stoffers et al. teach that treating HI, for example, may include but is not limited to lowering elevated blood glucose and stabilizing insulin levels in patients (para. [0137]). The reference further teaches various dose amounts (paras. [0117]-[0121]). Calabria et al disclose treatment of the same patient population and dosage regimen as disclosed in Example 6 of Stoffers et al. Subjects received an intravenous infusion of vehicle (0.9% NaCl) for 1 h followed by an intravenous infusion of exendin-(9-39) at 100 pmol/kg/min (0.02 mg/kg/h) for 2 h and then 300 pmol/kg/min (0.06 mg/kg/h) for 2 h, followed by 500 pmol/kg/min (0.1 mg/kg/h) for the last 2 h (p. 2586). Pai teach that the average weight of an adult in the US is 81 kg (pp. 860-861, 866). Per Stoffers et al, as evidenced by Calabria et al, using the average weight of adult (81 kg) administration of exendin(9-39) would equate to the following:
100 pmol/kg/min (0.02 mg/kg/h) for 2 h = 0.02 mg X 81 kg x 2 hr = 3.24 mg
300 pmol/kg/min (0.06 mg/kg/h) for 2 h = 0.06 mg x 81 kg x 2 hr = 9.72 mg
500 pmol/kg/min (0.1 mg/kg/h) for 2 h = 0.1 mg x 81 kg x 2 hr = 16.2 mg
This would provide a total dosage of 29.16 mg exendin(9-39). 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, 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). Accordingly, claim 10 is rendered obvious.
Regarding claims 13, 22, and 23, 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). Accordingly, aims 13, 22, and 23 are rendered obvious.
Regarding claim 24, Stoffers et al teach that the compositions can saline [reads on isotonic solution] (paras. [0107]-[0108], [0158]). Regarding claim 26, Stoffers et al teach that the compositions can include a buffer or preservative (paras. [0107]-[0109]).
Accordingly, claims 1, 2, 4, 5, 7, 8, 10, 12, 13, 22-24, and 26-32 are obvious in view of the teachings of the cited references.
Response to Arguments
Applicant traversed the rejection in the reply filed 11/03/2025 at pp. 9-11. Applicant asserts that the cited references do not teach or suggest a method of treating hyperinsulinemic hypoglycemia comprising a dose of 10-75mg of a recited exendin-4 derivative (reply at p. 10). Applicant asserts that Stoffers describes avexitide [also known as exendin(9-39)] for treating hyperinsulinemic hypoglycemia, list ranges of doses and frequencies as possibilities for dosing regimens, and polyethylene glycol forms may be used, but does not suggest the claimed exendin-4 derivatives. Id.
Applicant asserts that Seeley is not remedying the alleged deficiency of Stoffers (reply at pp. 10-11). Applicant asserts that Seeley relates to the use of GLP-1 antagonists for their ability to produce a sedative or anxiolytic effect in a subject. Applicant further asserts that the reference focuses on weight-based dosing, not the claimed dose of 10-75 mg. Id.
Applicant asserts that the cited references do not direct the skilled artisan to the claimed method, reciting specific combinations of elements (reply at p. 11). Applicant states: to arrive at the presently claimed regimen, a skilled person is required to “pick and choose” a specific exendin-4 derivative selected from the group of recited exendin-4 derivatives, administered at a specific dose range. Id. Applicant asserts that anticipation or obviousness cannot be based on “picking and choosing” disparate elements to reconstruct the claimed invention, referring to In re Arkley, In re Baird, and In re Jones (reply at p. 8).
Examiner has reviewed and considered applicants arguments but is not persuaded.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant focuses on the term avexitide which is merely another name for the compound exendin(9-39). Stoffers explicitly teaches administering exendin(9-39) [or pegylated exendin(9-390] to treat hyperinsulinemic hypoglycemia, as well as dosage amounts and routes of administration (e.g., paras. [0005], [027], [0044]-[0054], [0074]-[0077]), [0114]-[0122], examples).
Contrary to applicant’s assertions, the Seeley reference is not limited to GLP-1 antagonists and sedative/anxiolytic effects, and weight-based dosing. Examiner reminds applicant that patents and applications are relevant as prior art for all they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). Seeley expressly teaches that GLP-1 receptor antagonists include exendin (9-39) and exendin (3-39) through exendin (8-39), e.g., exendin (5-39) (para. [0043]). Seeley et al. taught that all of these exendin-4 derivatives are GLP-1 receptor antagonists. Thus, the prior art taught that exendin (3-39) through exendin (9-39) are functional equivalents.
Regarding applicant’s assertions of “picking and choosing”, substituting one functional equivalent for another would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”). Additionally, there are only 7 peptides- again, all of which are functional equivalents- thus 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. This 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., 550 U.S. 398, 402 (2007). See also In re Fout, 675 F.2d 297, 301 (C.C.P.A. 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”).
Applicant’s reliance on In re Arkley, 455 F.2d 586, 587 (C.C.P.A. 1972) is misplaced. The case states although “[s]uch picking and choosing may be entirely proper in the making of a 103, obviousness rejection . . . it has no place in the making of a 102, anticipation rejection.” Arkley, 455 F.2d at 587-88. The instant rejection is a §103 obviousness rejection, not a §102 rejection. Examiner further notes that the instant rejection is distinguishable and based on a combination of references. With regard to In re Baird and In re Jones, the cited references disclose specific species - not a genus - of functional equivalents, exendin(3-39), exendin(4-39), exendin(5-39), exendin(6-39), exendin(7-39), exendin(8-39), and exendin(9-39).
The rejection is maintained for at least the reasons set forth herein and those previously made of record. Please see the above rejection for specific details.
Claims 1, 2, 4-8, 10, 12, 13, 22-24, and 26-32 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 Calabria et al (Diabetes 61:2585-2591 (2012)- previously cited), in view of Pai (Pharmacotherapy 32: 856–868 (2012)- previously cited) and Seeley et al. (U.S. 2004/0116331- previously cited), as applied to claims 1, 2, 4, 5, 7, 8, 10, 12, 13, 22-24, and 26-32 above, and further in view of Franco et al. (Obes. Surg. 21:1458–1468 (2011)- previously cited). This rejection is maintained from the office action mailed 7/15/2025, but has been amended to reflect claims filed 11/03/2025.
The teachings of Stoffers et al., Calabria et al, Pai, and Seeley et al. are set forth above. Although Stoffers et al. teach gastric bypass surgery for obesity, the reference doesn’t explicitly teach types of gastrointestinal surgeries.
Franco et al. is a review article discussing the advantages and disadvantages of three bariatric surgeries: sleeve 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 Roux-en-Y gastric bypass and developed hyperinsulinemic hypoglycemia would be a suitable candidate for treatment with Exendin(5-39), as taught by Stoffers et al. and Seeley et al. The skilled artisan would have recognized that patients that have undergone bariatric procedures of sleeve gastrectomy and adjustable gastric banding could also be candidates for treatment with exendin(5-39).
Claims 1, 2, 4-8, 10, 12, 13, 22-24, and 26-32 are rendered obvious by the cited references.
Response to Arguments
Applicant traversed the rejection in the reply filed 11/03/2025 at pp. 11-12. Applicant asserts that the cited references do not teach or suggest a method of treating hyperinsulinemic hypoglycemia comprising a dose of 10-75mg of a recited exendin-4 derivative (reply at p. 11). Applicant asserts that Franco does not remedy the alleged deficiencies of the cited references (reply at p. 12). Applicant asserts that Franco “is cited for the purpose of describing various gastric surgeries”, and that the combination of cited references “fails to teach or suggest all limitations of claim 1”. Id.
Examiner has reviewed and considered applicants arguments but is not persuaded.
Examiner refers applicant to the above rebuttal arguments that pertain to this rejection as well. The rejection is maintained for at least the reasons set forth herein and those previously made of record. Please see the above rejection for specific details.
Claim(s) 1, 2, 4-8, 10, 12, 13, 19-24, and 26-32 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 Calabria et al (Diabetes 61:2585-2591 (2012)- previously cited), in view of Pai (Pharmacotherapy 32: 856–868 (2012)- previously cited), Seeley et al. (U.S. 2004/0116331- previously cited), and Franco et al., as applied to claims 1, 2, 4-8, 10, 12, 13, 22-24, and 26-32 above, and further in view of Veronese et al (Biodrugs 22: 315-329 (2008)- previously cited). This rejection is maintained from the office action mailed 7/15/2025, but has been amended to reflect claims filed 11/03/2025.
The teachings of Stoffers et al., Calabria et al, Pai, Seeley et al, and Franco are set forth above. Although Stoffers teaches pegylated forms of GLP-1 antagonists, the reference does not explicitly teach the limitations of instant claims 19-21.
Veronese et al is a review article discussing pegylation of biological therapies, including peptides and proteins, as well as methods of preparing pegylated conjugates (see Veronese et al generally). The term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency (abstract). Veronese et al teach conjugation of PEG at the N- or C- termini of peptides/proteins (e.g., pp. 317-320).
It would have been obvious to one of ordinary skill in the art to modify an exendin-4 derivative of Stoffers (or Seeley et al) with a PEG moiety at the N- or C- termini of the exendin-4 peptide. The skilled artisan would have recognized that Stoffers taught pegylated exendin(9-39) and that Veronese et al taught methods of preparing/modifying peptides to obtain peptide-PEG conjugates. The skilled artisan would have had a reasonable expectation of success because Veronese et al explicitly taught methods of preparing peptides comprising a PEG moiety at the N- and/or C- termini. Accordingly, claims 19 and 20 are rendered obvious.
Regarding claim 21, Veronese et al teach that PEG group sizes include 5-40 kD (Table 2, pp. 320-321).
Accordingly, claims 1, 2, 4-8, 10, 12, 13, 19-24, and 26-32 are obvious in view of the teachings of the cited references.
Response to Arguments
Applicant traversed the rejection in the reply filed 11/03/2025 at p. 12. Applicant asserts that the cited references do not teach or suggest a method of treating hyperinsulinemic hypoglycemia comprising a dose of 10-75mg of a recited exendin-4 derivative (reply at p. 11). Applicant asserts that Veronese does not remedy the alleged deficiencies of the cited references. Id. Applicant asserts that Veronese “is cited for the purpose of describing pegylation of various biological therapies ”, and that the combination of cited references “fails to teach or suggest all limitations of claim 1”. Id.
Examiner has reviewed and considered applicants arguments but is not persuaded.
Examiner refers applicant to the above rebuttal arguments that pertain to this rejection as well. The rejection is maintained for at least the reasons set forth herein and those previously made of record. Please see the above rejection for specific details.
Claims 1, 2, 4-8, 10, 12, 13, and 22-32 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 Calabria et al (Diabetes 61:2585-2591 (2012)- previously cited), in view of Pai (Pharmacotherapy 32: 856–868 (2012)- previously cited), Seeley et al. (U.S. 2004/0116331- previously cited) and Franco et al. (Obes. Surg. 21:1458–1468 (2011)- previously cited), as applied to claims 1, 2, 4-8, 10, 12, 13, 19-24, and 26-32 above, and further in view of Gurman et al (Expert Rev. Med. Devices 11:1–19 (2014)- previously cited). This rejection is maintained from the office action mailed 7/15/2025, but has been amended to reflect claims filed 11/03/2025.
The teachings of Stoffers et al., Calabria et al, Pai, Seeley et al., and Franco are set forth above. Although Stoffers et al. teach subcutaneous administration, the reference does not a pen-injector.
Gurman et al is a review article discussing the advantages of prefilled devices for parenteral applications, including pen injectors (abstract; p. 159-146). Pen injectors improve patient adherence to treatment because they are easy to use, self-administrated, generally painless and safe for the patient (p. 4). Pen injectors for diabetes have adopted to the extent that they are now the gold standard in diabetes management. Id. The reference further teaches a variety of commercially available pen injectors. See reference generally.
It would have been obvious to the skilled artisan to prepare a pen injector comprising the exendin-4 derivative. Gurman et al teach that pen-injectors comprising medications allow for ease-of-use and increased patient compliance for treatment. The skilled artisan would have had a reasonable expectation of success in preparing a pen injector because the devices were readily known and commercially available in the prior art. Accordingly, claim 25 is rendered obvious.
Claims 1