DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 3, 2026, has been entered.
Claim Interpretation
BRI of the “said pharmaceutical composition being free of additional compound(s) capable of protecting the protein active ingredient against degradation by digestive enzymes” consistent with the specification allows for buffering components but excludes additional compounds such as digestive enzyme inhibitors and components of physical protection systems such as a coating, a matrix, a capsule wall, such as a liposome enveloping the protein active ingredient and protecting it from degradation by digestive enzymes. This interpretation was acknowledged by Applicant in the response filed November 26, 2025.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 14 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 14 recites the limitation "a composition" in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 is a method for the oral treatment of a disease comprising administering a pharmaceutical composition. Therefore, claim 14, directed to a method for preparing a composition according to claim 1 lacks antecedent basis.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: mixing the compositions (i) and (ii) prior to administration. The mixing step is essential for the composition (ii) to buffer the pH of composition (i) and protect the composition (i) against degradation by digestive enzymes.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 is a method for the oral treatment of a disease comprising administering a pharmaceutical composition. Therefore, claim 14, directed to a method for preparing a composition according to claim 1 lacks fails to further limit and lacks all of the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1, 3-15, 17-33, 35, and 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Bennis et al. (US 8,309,123 B2) in view of Kalra et al. (A Review on Semaglutide: An Oral Glucagon-Like Peptide 1 Receptor Agonist in Management of Type 2 Diabetes Mellitus. Diabetes Ther (2020) 11:1965–1982).
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.
1. Determining the scope and contents of the prior art.
Claim 1: A method for the oral treatment of a disease…
Bennis et al. teach a method for treating a disease or disorder in a patient comprising orally administering to the patient a pharmaceutical composition (col 3, lines 20-28). To that end, Bennis et al. teach a means for protecting the active ingredient from being metabolized in the gastric and intestinal environment (col 3, lines 49-58).
…said pharmaceutical composition comprising: (i) a protein active ingredient, said protein active ingredient being a glucagon-like peptide-1 (GLP-1) receptor agonist..
Bennis et al. teach a pharmaceutical composition, in liquid or solid form, for administration by oral route of at least one protein active ingredient. Bennis et al. teach that "protein active ingredient" means a protein or peptide that substantially retains its biological activity after passage through the stomach and intestine (col 2, lines 55-67). Bennis et al. reduces to practice insulin and does not teach GLP-1R agonists.
… and (ii) a system that can buffer the pH of the pharmaceutical composition to a value ranging from 4 to 8…
Bennis et al. teach that the composition comprises at least one protein active ingredient, in free form, and, for a liquid, a buffer system that buffers it to a pH greater than 4 and less than or equal to 8 or, for a solid, a buffer system that exerts, when it is placed in a liquid medium, a buffer effect between a pH greater than 4 and a pH less than or equal to 8 (col 2, lines 55-67).
… said pharmaceutical composition being free of additional compound capable of protecting protein active ingredient against degradation by digestive enzymes.
Bennis et al. teach that the oral compositions contain one protein active ingredient in free form and a buffer system. The buffer system is effective in protecting said free form in the gastrointestinal tract. The active protein ingredient is “present as is or in a simple mixture with the excipients required for its formulation”. Bennis et al. teach that the oral compositions do not include a “physical system of protection, more or less complex, such as a coating, matrix or capsule wall (said active ingredient is not coated, matrixed or encapsulated (notably in liposomes), etc.)” (col 4, line 59 – col 5, line 7).
2. Ascertaining the differences between the prior art and the claims at issue.
In summary, Bennis et al. teach all limitations of instant claim 1 except for the GLP-1R agonist. The genus of protein active ingredients taught by Bennis et al. includes GLP-1R agonists. However, Bennis et al. does not explicitly disclose, suggest, or reduce to practice this subgenus or species. In contrast, Bennis et al. reduce to practice the protein active ingredient insulin. Bennis et al. teach that the oral formulation is applicable to other proteins such as somatotropin (human growth hormone) or a derivative thereof, calcitonin, or an LHRH (Luteinizing Hormone Releasing Hormone) analogue such as tryptoreline (col 5, line 62 – col 6, line 2).
3. Resolving the level of ordinary skill in the pertinent art.
In a 2020 review article, Kalra et al. teach that glucagon-like peptide 1 receptor agonists (GLP1 RAs) are a well-established class of glucose lowering drugs. Kalra et al. teach “GLP-1 RAs are preferred second-line agents in patients with T2DM with established atherosclerotic cardiovascular diseases (ASCVD) in light of their demonstrated ASCVD benefit, high efficacy, low potential for hypoglycaemia and potential for weight loss. More recently, the European Society of Cardiology (ESC) has deemed GLP-1 RAs to be the first-line therapy for cardiovascular risk reduction in patients with T2DM with very high/high risk” (p. 1966, col 1). Karla et al. teach that subcutaneous administration is a significant barrier to use and that as a result, an oral formulation has been developed (p. 1968, col 2):
Quite a few barriers have been identified related to injectable GLP-1 RA therapy. Patients’ perception of injectable therapy include perceived difficultly to use and fear of injections. This can have effects on the acceptance of therapy or adherence in a patient with type 2 diabetes. To overcome the barriers and to improve the adherence, oral GLP-1 RAs were needed, but oral protein-based drug absorption is limited because of degradation in the stomach due to low pH, proteolytic enzyme activity, and limited permeability across the gastrointestinal (GI) epithelium. The bioavailability of GLP-1 RAs administered orally alone is very low and, in order to avoid degradation, the active molecule has to be protected and delivered through the GI epithelium and into the bloodstream. Co-formulation of GLP-1 RA with an absorption enhancer is necessary to achieve adequate bioavailability after oral administration.
In summary, Kalra et al. teach that in response to the need for oral GLP-1Ras, a formulation containing semaglutide and an absorption enhancer was developed.
It would have been obvious to substitute the GLP-1Ras taught by Kalra et al. for the protein active ingredient in the oral formulation taught by Bennis et al. and to use it in an oral method of treatment. The resulting method would comprise orally administering a formulation containing GLP-1RA as the protein active ingredient, in free form, and, for a liquid, a buffer system that buffers it to a pH greater than 4 and less than or equal to 8 or, for a solid, a buffer system that exerts, when it is placed in a liquid medium, a buffer effect between a pH greater than 4 and a pH less than or equal to 8 , satisfying all of the limitations of claim 1. One of ordinary skill in the art would have been motivated to do so given that Kalra et al. describe an art-recognized need for oral GLP-1RA therapies. In addition, one of ordinary skill in the art would recognize that the formulation of Bennis et al. is designed to solve the same problem identified in Kalra et al., namely the effect of gastric and intestinal degradation on protein and peptide-based drugs. There would have been a reasonable expectation of success given that Bennis et al. reduce to practice at least one protein, insulin, and also teach that the system is suitable for very different proteins such as somatotropin (human growth hormone) or a derivative thereof, calcitonin, or an LHRH (Luteinizing Hormone Releasing Hormone) analogue such as tryptoreline (col 5, line 62 – col 6, line 2).
Regarding claims 3, 5, and 17, Kalra et al. teach that the GLP-1Ras include exenatide, lixisenatide, liraglutide, albiglutide, semaglutide, and dulaglutide (Table 1; Figure 1).
Regarding claims 4 and 39, Kalra et al. teach GLP-1Ras, including oral semaglutide, can be used to treat metabolic diseases such as type 2 diabetes (p. 1978, col 2).
Regarding claim 6, Bennis et al. teach that the oral formulation is in liquid or solid form (col 2, lines 55-67).
Regarding claim 7, Bennis et al. teach that the buffer is chosen among phosphate, acetate, maleate, phthalate, succinate, citrate, imidazole, tetrabutylammonium, 2-amino-2-hydroxymethyl-1,3-propanediol (or trihydroxymethylaminomethane or Trometamol or Tham or Tris), tris-glycine, barbitol, tris-EDTA BSA, copper sulfate and zwitterionic buffers (col 6, lines 13-20).
Regarding claims 8, 18, and 19, Bennis et al. teach that the pH is 4.5 to 7.5, 5 to 7, or 6.5 (col 5, lines 30-36), which are the same as/fall within the claimed ranges of pH.
Regarding claim 11, Kalra et al. do not teach that the oral GLP-1RA formulations should further comprise insulin or other protein active ingredients.
Regarding claims 13, 35, and 37, Bennis et al. reduce to practice an effervescent tablet containing the protein active ingredient and a buffer system that is a combination of 1142.7 mg anhydrous monosodium citrate anhydrous, 2076 mg sodium bicarbonate, 152.60 mg sodium benzoate, and 120 mg monosodium phosphate and disodium phosphate in a tablet of theoretical weight of 3.5 g, to yield pH 6.8 in solution (Tablet B, col 8). Bennis et al. teach that the buffer system is effective in vitro and in vivo to preserve the activity of the protein active ingredient against pepsin and trypsin, demonstrating that the formulation is suitable for oral delivery (col 12, lines 40-62). Kalra et al. teach that the oral semaglutide formulation contains 3, 7, or 14 mg of semaglutide (p. 1978, col 2).
The formulation resulting from the combination of Bennis et al. and Kalra et al. would contain
(i) 120 mg monosodium phosphate and disodium phosphate,
(ii) 1142.7 mg anhydrous monosodium citrate anhydrous,
(iii) 2076 mg sodium bicarbonate,
(iv) 152.60 mg sodium benzoate, and
in a tablet of theoretical weight of 3.5 g, to yield pH 6.8 in solution as taught by Bennis et al. (Tablet B, col 8)
and
(v) 3, 7, or 14 mg of the GLP-1 peptide as taught by Kalra et al. (p. 1978, col 2). Each of these amounts falls within the claimed ranges.
Regarding claims 12 and 25-33, formulation resulting from the combination of Bennis et al. and Kalra et al. would contain as percentage by mass relative to the total mass of the tablet (3.5 g)
0.120 g/3.5 g x 100 = 3 % monosodium phosphate and disodium phosphate
1.1427 g/3.5 g x 100 = 33 % anhydrous monosodium citrate anhydrous,
2.076 g/3.5 g x 100 = 59 % sodium bicarbonate,
0.15260 g/3.5 g x 100 = 4 % sodium benzoate, and
0.003, 0.007, or 0.014 g/3.5 g x 100 = 0.086 – 0.4% of the GLP-1 peptide. Each of these percentages fall within the claimed ranges.
Regarding claim 14, Bennis et al. teach a method of making the oral compositions comprising mixing the active agent with a buffer system that can buffer the pH to 4 to 8 (col 3, lines 9-18).
Regarding claims 15, broadest reasonable interpretation of “kit” includes the formulations prepared from the combined teaching of Bennis et al. and Kalra et al., which include the same components, the GLP-1 peptide and the buffer.
Regarding claims 9-10 and 20-24, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Each of the properties recited in claims 9-10 and 20-24 would flow from the combination of the oral formulation of Bennis et al. and the active ingredient semaglutide of Kalra et al.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The arguments and declaration under 37 CFR 1.132 filed February 3, 2026, are sufficient to overcome the rejection of claims 34, 36, and 38, but are insufficient to overcome the rejection of all other claims.
Example 4 of the specification provides a comparison between semaglutide in the formulation of the instant claims and semaglutide as described by Kalra et al. (Rybelsus®):
The data show complete protection of semaglutide in simulated gastric medium in the presence of pepsin and with the buffer system (Table 7). In the absence of pepsin, semaglutide is also stable in the presence of the buffer system (Table 7). The results show that in the absence of pepsin, Rybelsus is only stable at a level of 78% for 1 hour in gastric medium and is only maintained at a level of 16% after 2 hours (Table 8). The semaglutide formulated in Rybelsus is completely and immediately degraded by pepsin in a simulated gastric medium and without a buffer system (Table 8). Thus, the pharmaceutical composition of the invention allows to protect the product Rybelsus from acidity in the gastric medium and from pepsin.
The data in Example 4 establish that the claimed buffer system is protective of semaglutide under conditions relevant for oral delivery and that the buffer system is superior in this assay to semaglutide formulation taught by Kalra et al. The buffer system in Example 4 of the specification is functioning as it was intended and as it was previously shown in Bennis et al. to function for another protein active agent, insulin. In the declaration under 37 CFR 1.132 on February 3, 2026, Dr. Farid Bennis provided evidence that the same buffer system was unable to protect a different peptide, calcitonin, from digestive enzymes. This evidence establishes that the effectiveness of the prior art buffer system is dependent on the active pharmaceutical ingredient (API) and does not necessarily extend to all other APIs, including semaglutide. Therefore, the results in the specification and declaration are unexpected and sufficient to overcome the prima facie case of obviousness for claims 34, 36, and 38.
MPEP 716.02(d) states: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
In the instant case, the evidence relied upon which establishes unexpected results for claims 34, 36, and 38 was obtained for an embodiment with a single buffer system consisting of (i) 120 milligrams (mg) of monosodium phosphate dihydrate, (ii) 1142 mg of anhydrous monosodium citrate,(iii) 2076 mg of sodium bicarbonate, and (iv) 157 mg of sodium benzoate, and a single API, the GLP-1 agonist semaglutide. The evidence does not establish that the full scope of the claims with respect to the API and buffer system would exhibit the same results unexpected in view of Bennis. The evidence relied upon is representative of the full scope of APIs, including other GLPs, buffer system components and their amounts. Therefore, the rejection is maintained for claims 1, 3-15, 17-33, 35, and 37-39.
For these reasons, the rejection is maintained.
Allowable Subject Matter
Claims 34, 36, and 38 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654