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 .
DETAILED ACTION
Examiner acknowledges receipt of the reply filed 7/22/2025, in response to the non-final office action mailed 4/28/2025.
Claims 1, 5, 7, and 10-14 are pending. Claims 12-14 are newly added.
Claims 1, 5, 7, and 10-14 are being examined on the merits in this office action.
Examiner comment
New claims 12-14 were improperly amended. New claims should not have underlined claim language.
For example, claim 12 should have been presented as:
Proper: 12. (New) A stable oral formulation comprising: ….
Wrong: 12. (New) a stable oral formulation comprising: …
In reply to this office action, if any new claims are presented, do NOT underline the claim language.
Additionally, in reply to this office action, applicant is required to explicitly indicate where in the as-filed specification support for further claim amendments is found.
Claim Objections-withdrawn
The objection of claims 1 and 7 is withdrawn in view of the amendment filed 7/22/2025.
Claim Rejections - 35 USC § 112- withdrawn
The rejection of claim 11 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment filed 7/22/2025.
Claim Rejections - 35 USC § 103- withdrawn
The rejection of claims 1, 5, 7, 10, and 11 under 35 U.S.C. 103 as being unpatentable over Sauerberg et al. (U.S. 2018/0360918- previously cited), and further in view of Cumming et al (U.S. 2003/0091623- previously cited), as evidenced by Twarog et al. (Pharmaceutics 11, 78 pp. 1-21 (2019)- previously cited) and Coughlan et al (U.S. 2011/0182985- previously cited as relevant art not relied upon), is withdrawn in view of the amendment filed 7/22/2025.
Response to Arguments
Applicant’s arguments and amendment filed 7/22/2025 with respect to the above objection and rejections have been fully considered and are persuasive. The objection and rejections have been withdrawn.
A new grounds of objection and rejection is set forth in view of the amendment filed 7/22/2025.
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.
New Objections/Rejections
Trademark in the Specification – New objection
The use of trademark BRIJ 35 has been noted in this application at least at pp. 26 of the as-filed specification. They should be capitalized wherever they appear and be accompanied by the generic terminology. Although the use of trademarks is permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as trademarks.
See also claims 1 and 12.
Claim Objections- New Objection
Claims 1, 7, and 10-14 are objected to because of the following informalities: This is a new objection necessitated by the amendment filed 7/22/2025.
Claim 1 should be amended to recite:
“a tablet or a capsule”
and wherein the oral pharmaceutical formulation does not contain a total of 0.42% with[[/]]75% relative humidity; and at least 80% of the semaglutide releases within 15 minutes in [[a]] 500 ml of phosphate , using USP apparatus II with a paddle speed of [[at]] 70 rpm.
The wherein clause set forth above, should be moved down 1 line in the claim to separate the clause from “SNAC”.
The claim term BRIJ is a trademark term. The term should be removed from the claim and rewritten with the generic name of the compound. The acronym “USP” should be written out in first order of appearance in the claims. The claim should be further clarified exactly what applicant is referring to by reciting “USP apparatus II”.
Claims 7 and 10 should be amended to recite “comprising [[the]] steps [[of]]”
Claim 10 should be amended to delete the extra spaces:
b) binder in [[ ]]water;
f) into a capsule shell[[ ]].
Claim 11 should be amended to recite “component” in singular format, not plural format of “components”. The claim should be rewritten to improve grammar and coherency.
Claim 12 should be amended to incorporate similar amendments as set forth for claim 1. The wherein clause at step v) should be moved down one line to start a new clause for the claim.
Claims 12-14 should be amended to recite cellulose
Claims 13 and 14 should be amended to recite “A[[The]] stable oral pharmaceutical formulation”.
Appropriate correction is required.
Examiner requests that applicant thoroughly review the claims for grammar and typographical errors.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5, 7, and 10-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new rejection necessitated by the amendment filed 7/22/2025.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient” (MPEP § 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure (MPEP § 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
The instant claims are drawn to a stable oral pharmaceutical formulation comprising i) semaglutide; ii) permeation enhancer comprising a combination of least two selected from the group consisting of arginine, sodium caprylate, sodium caprate, tryptophan and 10O-Hydroxy-N-[(4-hydroxy-3 methoxyphenyl)methyl]decanamide in an amount from 40% to 98% w/w of the oral pharmaceutical formulation; and iii) one or more other excipients in an amount from 1% to 30% w/w of the oral pharmaceutical formulation; and wherein a permeation enhancer enhancers is not sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC); and wherein the oral pharmaceutical formulation in the form of tablet or capsule; and wherein the oral pharmaceutical formulation contains not more than 0.42% of total impurities by weight relative to semaglutide after storage for 3 months at 40°C/75% relative humidity and at least 80% of the semaglutide releases within 15 minutes in a 500 ml of Phosphate buffer pH 6.8 with 0.05% Brij 35 at 37 °C using USP apparatus II with paddle speed at 70 rpm. Claim 5 recites a Markush grouping of excipients. Claims 7 (and 11) is drawn to a method of preparing the stable oral formulation of claim 1. Claim 10 is drawn to a process for the preparation of a stable oral pharmaceutical formulation of claim 5. Claims 13 and 14 depend from claim 1, and recite formulations and amounts of the recited compounds.
Claim 12 is drawn to a stable oral pharmaceutical formulation comprising: i) 0.2-50 mg of semaglutide; ii) 50-400 mg of permeation enhancer comprising a combination of at least two selected from the group consisting of arginine, sodium caprylate, sodium caprate, tryptophan and 10-Hvdroxv-N-[(4-hvdroxv-3-methoxvphenyl)methylldecanamide; iii) 4-10 mg of povidone; iv) 72-216 mg of microcrystalline cellullose; and v) 2-4 mg of magnesium stearate; and wherein a permeation enhancer is not sodium N-[8-(2- hydroxybenzoylaminolcaprylate (SNAC); and wherein the oral pharmaceutical formulation in the form of tablet or capsule; and wherein the oral pharmaceutical formulation contains not more than 0.42% of total impurities by weight relative to semaglutide after storage for 3 months at 40°C/75% relative humidity and at least 80% of the semaglutide releases within 15 minutes in a 500 ml of Phosphate buffer pH 6.8 with 0.05% Brii 35 at 37 °C using USP apparatus II with paddle speed at 70 rpm.
The issue at question is whether a person of ordinary skilled in the art would be able to determine what structural features (combination of compounds - semaglutide, permeation enhancers, and other excipients, as well as dosage amounts of each compound) is required for the instant claimed stable oral pharmaceutical formulation to have the functional characteristics of the recited impurities and semaglutide release profile following storage of the pharmaceutical formulation for 3 months.
(a) actual reduction to practice and (b) disclosure of drawings or structural chemical formulas:
In the instant case, the instant specification discloses 3 semaglutide formulations, Examples 1, 5, and 7.
The examples are limited to specific compounds and amounts of each compound. Example 5 is the only example relating to impurities and semaglutide release profile following storage of the semaglutide pharmaceutical formulation. The dissolution profile is disclosed at pages 26-27 (Tables 2-3). The denoted pages and tables provide support for the claim limitations:
wherein the oral pharmaceutical formulation contains not more than 0.42% of total impurities by weight relative to semaglutide after storage for 3 months at 40°C/75% relative humidity and at least 80% of the semaglutide releases within 15 minutes in a 500 ml of Phosphate buffer pH 6.8 with 0.05% Brii 35 at 37 °C using USP apparatus II with paddle speed at 70 rpm.
The specification does not provide support for the entirety of the instant claim scope of independent claims 1 and 12. The claim limitations are limited to a single formulation:
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Taken all these together, the instant specification does not describe a general correlation between structure and function for the claimed genus of stable oral pharmaceutical formulation comprising semaglutide (and other recited compounds and amounts thereof) having the of features of the claimed impurities and dissolution profile.
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure:
As discussed above, in the instant case, based on the disclosure of instant specification, other than the formulation disclosed in Example 5, a person of ordinary skilled in the art would not be able to determine what structural compounds (semaglutide, permeation enhancers, and other excipients- much less the specific combination and amounts thereof) is required for the claimed properties of impurities and dissolution profile following storage of the formulation after 3 months.
Furthermore, the present application is attempting to patent what has not yet been invented and the fact that one of skill in the art can test for the effect used to determine the compounds does not necessarily confer sufficient written description. The claimed stable oral pharmaceutical formulations would entail testing limitless potential combinations of compounds, and one of skill in the art could afterwards still be faced with no hits with the desired functionality.
Therefore, based on the state of art, a person of ordinary skilled in the art would not be able to determine what combination of compounds is required for the claimed impurities and dissolution profile following storage of the formulation after 3 months.
(d) representative number of samples:
In the instant case, the genus of instant claimed stable oral pharmaceutical formulations encompasses numerous semaglutide, permeation enhancers, and other excipients with distinct chemical and physical properties.
And, as discussed in (a) and (b) above, the instant specification is limited to the formulation of example 5. The claimed impurities and semaglutide dissolution profile limitations cannot be extrapolated to other formulations, comprising distinct compounds and amounts thereof.
Considering the scope of the genus of instant claimed stable oral pharmaceutical formulations, the instant specification fails to provide sufficient examples to describe the entire genus of stable oral pharmaceutical formulations claimed.
Taken all these together, considering the state of the art and the disclosure in instant specification, it is deemed that the instant specification fails to provide adequate written description for the claimed genus of stable oral pharmaceutical formulations comprising semaglutide, permeation enhancers and other excipients with the claimed features of impurities and dissolution profile following storage for 3 months. The recited claim limitations relating to impurities and semaglutide dissolution profile are limited to the semaglutide formulation of example 5; and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 12 and 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new rejection necessitated by the amendment filed 7/22/2025.
Applicant’s amendment of 07/22/2025 constitutes new matter.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Scope of the claimed genus
Claim 12 is directed to a stable oral pharmaceutical formulation comprising: i) 0.2-50 mg of semaglutide; ii) 50-400 mg of permeation enhancer comprising a combination of at least two selected from the group consisting of arginine, sodium caprylate, sodium caprate, tryptophan and 10-Hvdroxv-N-[(4-hvdroxv-3-methoxvphenyl)methylldecanamide; iii) 4-10 mg of povidone; iv) 72-216 mg of microcrystalline cellullose; and v) 2-4 mg of magnesium stearate; and wherein a permeation enhancer is not sodium N-[8-(2- hydroxybenzoylaminolcaprylate (SNAC); and wherein the oral pharmaceutical formulation in the form of tablet or capsule; and wherein the oral pharmaceutical formulation contains not more than 0.42% of total impurities by weight relative to semaglutide after storage for 3 months at 40°C/75% relative humidity and at least 80% of the semaglutide releases within 15 minutes in a 500 ml of Phosphate buffer pH 6.8 with 0.05% Brii 35 at 37 °C using USP apparatus II with paddle speed at 70 rpm.
Claim 13 is directed to a stable oral pharmaceutical formulation according to claim 1, comprising: i) 3-14 mg of semaglutide; ii) 50-100 mg of arginine; iii) 100-250 mg of sodium caprylate; iv) 4-10 mg of povidone; v) 72-216 mg of microcrystalline cellulose: and vi) 2-4 mg of magnesium stearate.
Assessment of whether species are disclosed in the original specification
The specification discloses 3 formulations comprising semaglutide with distinct amounts of the recited compounds in Examples 1, 5, and 7. However, claims 12 and 13 recite ranges of components, e.g., 0.2-50 mg semaglutide, 50-400 mg permeation enhancer, 72-216 mg of microcrystalline cellulose, etc. Applicant is picking and choosing claim ranges to arrive at instant claims 12 and 13 that were never taught as an embodiments in the as-filed specification. Moreover, the recited formulations do not correlate with the claimed limitations of impurities and semaglutide release rates after 3 months storage. The functional limitations (impurities and release rates) are limited to a specific semaglutide formulation taught in Example 5 (as-filed specification at pp. 25-26).
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, the specification does not carve out a specific sub-genera of the recited semaglutide formulations recited in claims 12 and 13. There is no support in the specification that supports any preference for this sub-genera than that of the greater genera of a stable oral pharmaceutical composition comprising semaglutide as recited in claim 1.
Identifying characteristics and structure/function correlation
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe the structural, physical and/or chemical properties of the sub-genera. There are no distinguishing factors anywhere in the specification that would direct the skilled artisan to the specific sub-genera of stable oral pharmaceutical composition comprising semaglutide recited in claims 12 and 13, as compared to the greater genera of a stable oral pharmaceutical composition comprising semaglutide, as recited in claim 1.
In conclusion, for these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Examiner expressly notes that claim 14 is not rejected as being new matter because it appears to have support from the formulation of Example 7.
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 5, 7, and 10-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a new rejection necessitated by the amendment filed 7/22/2025.
Claim 1 recites the limitation "the oral pharmaceutical formulation" twice at line 10. There is insufficient antecedent basis for this limitation in the claim. To overcome the rejection, the claim should be amended to recite “the stable oral pharmaceutical formulation”.
Claim 1 recites the limitation "the form". There is insufficient antecedent basis for this limitation in the claim.
Claim 1 contains the trademark/trade name BRIJ 35. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the chemical and, accordingly, the identification/description is indefinite.
Because claims 5, 7, 10, 11, 13 and 14 depend from indefinite claim 1 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
Claims 7 and 10 recite the limitation "the steps" at line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 10 recites the limitation "the preparation" at line 1. There is insufficient antecedent basis for this limitation in the claim.
Regarding claims 10 and 11, the phrase "such as" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 12 contains the trademark/trade name BRIJ 35. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the chemical and, accordingly, the identification/description is indefinite.
Claim 12 recites the limitation "the oral pharmaceutical formulation" twice in the claim. See p. 3, ll. 7-8 There is insufficient antecedent basis for this limitation in the claim. To overcome the rejection, the claim should be amended to recite “the stable oral pharmaceutical formulation”.
Claim 12 recites the limitation "the form". There is insufficient antecedent basis for this limitation in the claim.
The metes and bounds of claim 14 are deemed to be indefinite. Claim 14 recites the term “compound 14”. It is unclear as to what applicant intends by this term. It appears that claim 14 recites the composition set forth in Example 7. To overcome this rejection, Applicant should amend claim 14 to recite the specific chemical name of “compound 14”.
Relevant Art Not Relied Upon
Sauerberg et al. (U.S. 2018/0360918- previously cited), teach solid pharmaceutical compositions for oral administration comprising semaglutide and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, e.g., sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) (e.g., paras. [0007]-[0019], [0033]-[0041], [0058], [0071]-[0080], Example 1. See Table 1 for example of formulation). SNAC [reads on permeation enhancer/delivery agent] can comprise at least 60% (w/w), such as at least 70% (w/w) or at least 75% (w/w), delivery agent (e.g., paras. [0035]-[0036], [0085], [0114]). The composition can comprise at least 1-30% other excipients, e.g., composition comprises at least 60% (w/w) delivery agent, less than 10% (w/w) binder, 5-40% (w/w) filler, and less than 10% (w/w) lubricant and/or glidant (para. [0114]). The composition can comprise 0.1-10% (w/w), such as 0.2-4% (w/w) or 0.5-3% (w/w), 1% (w/w) or 2% (w/w) of binder [e.g., povidone] (e.g., paras. [0105]-[0107]). The composition can comprise 5-40% (w/w), such as 10-30% (w/w) or 5-25% (w/w), 10.9% (w/w) or 18%(w/w) of filler, or comprises 19.5% (w/w) or 20.5% (w/w) of filler [e.g., avicel, such as avicel PH 102 or avicel PH 200 (microcrystalline cellulose] (e.g., paras. [0108]-[0110]). The composition can comprise 0.1-10% (w/w), 0.5-5% (w/w), 1-3.5% (w/w) or 1% (w/w) lubricant and/or a glidant [e.g., magnesium stearate]. (e.g., paras. [0111]-[0113]). The reference does not explicitly teach other permeation enhancers, such as sodium caprylate or sodium caprate.
Drucker (Nat Rev Drug Discov. 19:277-289 (2020)- previously cited) is a review article discussing advancements in oral peptide therapeutics. Oral delivery is especially desirable, but it faces substantial barriers related to the structural organization and physiological function of the gastrointestinal tract. The reference highlights strategies designed to overcome these barriers, including permeation enhancers, inhibitors of gut enzymes, and mucus-penetrating and cell-penetrating peptides. The reference discusses clinical trials, including insulin, calcitonin, parathyroid hormone and vasopressin (abstract). Key considerations in evaluating the suitability of oral peptide formulations include the extent of absorption across the intestinal mucosa, the achievement of detectable pharmacodynamic activity and systemic bioavailability (p. 279). Permeation enhancers can target either the transcellular route, by facilitating the passage of non-degraded peptides through epithelial cells, or the paracellular route, via interference with the function of intercellular junctional and adhesion proteins — for example, with chelators that sequester calcium, which is simultaneously needed for E-cadherin function and as a cofactor for some proteases. Id. Permeation enhancers include medium-chain fatty acids- sodium caprate, sodium caprylate, and SNAC. The reference teaches other factors for consideration- modulation of pH, enzyme inhibition, and cell-penetrating peptides (pp. 279-280. Drucker teaches that oral semaglutide was approved by the FDA in September 2019 (p. 284).
Maher et al (Drug discovery today technologies 9:e113-e119 (2012)-previously cited) teach that there is considerable interest in delivery platforms that improve oral bioavailability of poorly absorbed peptides, proteins and macromolecules. Not only does the oral route improve patient compliance, but reformulation can also extend intellectual property and reduce costs associated with sterile manufacturing and use of healthcare professionals. The oral route is also a more physiological means of delivering certain molecules to liver and intestinal cell targets (e.g. insulin and glucagon-like peptide-1 (GLP-1)) (e113). One of the simplest approaches to overcome poor oral macromolecule permeability is use of absorption enhancers which increase intestinal permeability as against impacting on molecule solubility. They do this by either opening epithelial tight junctions (TJs) (paracellular route), mildly perturbing the mucosal surface (transcellular permeation enhancement), or by non-covalent complexation with the payload. Several formulations that use enhancers have progressed to clinical trials to boost oral bioavailability of BCS Class III drugs (high solubility, low permeability). Id. Oral formulations of peptides using enhancers have reached clinical phases (Table 1). Other macromolecules in development for oral delivery include heparins, antibiotics, anticancer agents and ONS. Peptides are labile in gastrointestinal fluids and they need protection from degradation by gastric and pancreatic juice, and this can be achieved by enteric coating with pH-dependent methacrylate-based polymers. An entrapped formulation also enables co-release of peptidase inhibitors, mucoadhesives or absorption enhancers in specific intestinal regions (e114). Medium chain fatty acids have a long history of safe use as dietary constituents in human, and have been extensively studied as oral enhancers. C10 remains the only enhancer that has been used clinically in the intestine for that purpose (e115). Isis Pharma (USA) has also designed a different enteric-coated formulation of C10 to improve bioavailability of antisense ONS. Id. TPE (Chiasma, Israel) is an enteric-coated formulation containing sodium caprylate (C8) in hydrophilic microparticles that are mixed with castor oil or medium chain glyceride (MCG) and/or caprylic acid, yielding an oily suspension. Chiasma was granted orphan status by the FDA for their oral format of the octapeptide, octreotide (Octreolin) (e116).
Kamei et al (Pharmaceuticals 10:182, pp.1-21 (2018)-previously cited) advancements of arginine and tryptophan as absorption enhancers [permeation enhancers] for oral delivery of biopharmaceuticals, including peptide therapeutics, e.g. insulin and GLP-1 analogs (abstract). Cationic arginine and hydrophobic tryptophan have been reported to be key component amino acids for cellular internalization of CPPs. L-arginine could increase the oral delivery of insulin in its single amino acid form. Therefore, in the present study, we evaluated the ability of another key amino acid, tryptophan, to enhance the intestinal absorption of biopharmaceuticals. We demonstrated that co-administration with L-tryptophan significantly facilitated the oral and intestinal absorption of the peptide drug insulin administered to rats. Furthermore, L-tryptophan exhibited the ability to greatly enhance the intestinal absorption of other peptide drugs such as glucagon-like peptide-1 (GLP-1), its analog Exendin-4 and macromolecular hydrophilic dextrans (abstract). Artificial cationic peptides such as octaarginine (R8) are CPPs that have shown the greatest potential to act as bioavailability enhancers for facilitating mucosal absorption of poorly absorbable peptides and proteins (pp. 1-2). the relationship between chain length of arginine peptides and their ability to enhance the intestinal absorption of insulin and confirmed that the effect of R8 was stronger than that of shorter or longer peptides (p, 2). We recently found that the L-form of the amino acid arginine (L-arginine) could strongly enhance the intestinal absorption of insulin in its single amino acid form, although its effectiveness was relatively less than peptide forms of arginine. Id. Studies suggest that when hydrophobic moieties such as stearyl groups or hydrophobic amino acids such as tryptophan are found within the peptide structure they synergistically enhance the potential of the original arginine-rich peptides (p. 2). Table 1 teaches results of formulation comprising a peptide, L-t tryptophan and sodium caprate (C10) (p.11-13). Tryptophan singly improves the intestinal absorption of various biopharmaceuticals having peptide to protein molecular sizes. When examining the absorption of insulin in particular, the bioavailability enhancement effect of L-tryptophan was far stronger than that of L-arginine (p. 18).
Thus, Kamei et al expressly taught that arginine and tryptophan were effective permeation enhancers for oral delivery of peptide therapeutics.
Conclusion
No claims are allowed.
Claims 1, 5, 7, and 10-14 are pending and are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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