DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after May 13, 2026, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ claimed invention filed on 05/13/2026 in the matter of Application N° 18/060,766. Said documents are entered on the record. The Examiner further acknowledges the following:
Claims 32 and 35 are withdrawn. Claim 16 is cancelled. No claims have been added.
Claims 1, 3, 11, 15, 21-24, 26, 28-31, and 36-38 are pending.
No new matter has been added.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3, 11, 15, 21-24, 26, 28-31, and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Geschwind et al. (US20190328666) in view of Gudrun et al. (US2017087096).
Geschwind et al. teaches a pharmaceutical composition (See 0069). Pharmaceutically acceptable compositions that contain an ionic association complex involving an active pharmaceutical component and a carrier (See 0034). In this context, “pharmaceutically acceptable carrier” refers to a solvent encapsulating material that is employed to convey or transport the subject compound (See 0073). By reacting the purified molecule in its free acid form with a pharmaceutically acceptable metal cation, compositions of the present invention that comprise one or more acidic functional groups may produce pharmaceutically acceptable salts with pharmaceutically acceptable bases (See 0076). Active ingredient which can be combined with a carrier material (See 0077). To provide for greater stability, compositions can include additional carriers, such as liposomes or micelle-forming substances, like bile acids (See 0084). Using liposomes, the active component is formulated to release the active ingredient gradually or under control. If necessary, the active ingredient may also be microencapsulated with one or more of the excipients mentioned above (See 0105). The immediate specification states that “the active pharmaceutical ingredient-cationic carrier ionic association complex comprises a liposome” (page 3, lines 8-9). The active component in a liposome is seen as an ionic association complex between the therapeutic substance and the carrier, is a derivative of β-cyclodextrin (See 0008). The cyclodextrin is β-cyclodextrin. Wherein the β-cyclodextrin encapsulates the active pharmaceutical ingredient carrier ionic association complex (See 0068). The pharmaceutical compositions comprising selective inhibitors of ATP production described above encapsulated within inert or modified cyclodextrins, to form a β-cyclodextrin-active pharmaceutical ingredient -carrier inclusion complex (See 0024). Anionic moieties on cyclodextrins force the halogen atom (e.g., bromine) of a halopyruvate (e.g., 3 BrPA) to sit in the cavity. It was established that cyclodextrins encapsulate 3-BrPA in a form that protects and stabilizes 3-BrPA (See 0102). Complexes can be obtained by agitating and mixing the cyclodextrin (e.g., a solution containing the cyclodextrin) upon once the therapeutic agent is added dropwise (e.g., a solution containing the selective inhibitor of ATP production) see instant specification page 38 line 12-14 “Inclusion complex” or an “inclusion compound” refers to a chemical complex in which one chemical compound (the host) has a cavity into which a “guest” compound can be accommodated. An inclusion complex is formed by mixing β-cyclodextrin with the active agent because the cyclodextrin encapsulates the active agent in its cavity, but does not teach a specific example or embodiment wherein the active ingredient is combined with a carrier in an ionic association complex. However, Geschwind et al. teaches that the active ingredient may be encapsulated or entrapped in a liposome (See 0084). Formulated so as to provide slow or controlled release of the active ingredient therein using liposomes active ingredient can also be in microencapsulated form, with one or more of the above-described excipients (See 0105). Entrapping the drug in liposomes, see instant specification page 3 line 8-9. The active pharmaceutical ingredient-cationic carrier ionic association complex comprises a liposome, a liposome containing the active ingredient is interpreted as a pharmaceutical ingredient-cationic carrier ionic association complex. Therefore, it would have been obvious to one of ordinary skill in the art prior to the instant effective filing date through routine experimentation to use a liposome to encapsulate the active agent taught by Geschwind et al. to serve as an active pharmaceutical ingredient-carrier ionic association complex to provide a controlled release of the active agent.
Regarding claim 3, Geschwind et al. teach the β-cyclodextrin or its derivative is contained in the pharmaceutical composition in amounts ranging from about 2% to about 10% by weight, but this is not explained in the pharmaceutical composition of claim 1. However, Geschwind et al. instructs that the active drug to cyclodextrin ratio should be at least 5:1 (See 0068). A selective inhibitor of ATP generation may have a 1:1 ratio to cyclodextrin, meaning that one inhibitor molecule and one cyclodextrin molecule can form a complex. On the other hand, the ratio may be 2:1, 3:1, 4:1, 5:1, or higher. Therefore, it would have been obvious to one of ordinary skill in the art prior to the instant effective filing date through routine experimentation to use the composition taught by Geschwind et al. wherein the ratio of active agent: cyclodextrin is greater than 5 to produce a composition containing 2-10% β-cyclodextrin so that more active agent is encapsulated in each cyclodextrin.
Regarding claim 15, Gudrun et al. teach insulins are administered parenterally. Non-invasive administration routes like oral delivery of insulin are investigated but there are several hurdles, as such enzymatic degradation in the drug efflux pumps, gastrointestinal tract, insufficient and variable absorption from the intestinal mucosa, as well as first pass metabolism in the liver (See 0003). Proteolysis of insulin glulisine encapsulated in protamine nanocapsules upon incubation in FeSSIF V2 at pH 5.8, 37° C. A original prototypes (protamine nanocapsules with no polysialic acid coating) and B prototypes post-coated with polysialic acid (See 0230, fig. 6).
Regarding claims 21, 22, and 23, Gudrun et al. teach a vial containing a defined pharmaceutical formulation and (ii) further a tablet, capsule, powder or any other oral dosage form which contains at least one further active pharmaceutical ingredient. The kit may further comprise a package leaflet with instruction for how to administer the pharmaceutical formulation and the at least one further active pharmaceutical ingredient (See 0173). Gudrun et al. discloses liquid pharmaceutical compositions comprising at least one insulin peptide, at least one semi-polar protic organic solvent and at least two non-ionic surfactants (See 0004). Pharmaceutical formulations are prepared by uniformly bringing the active pharmaceutical ingredient into association with a liquid carrier or finely divided solid carrier or both, and then shaping the product into the desired formulation. The pharmaceutical formulation includes enough of the active pharmaceutical ingredient to produce the desired effect upon the progress or conditioning of diseases. Formulation may refer to a solution as well as to a suspension or to an emulsion. The terms formulation and composition are meant to be synonyms, i.e., have identical meaning. The pharmaceutical compositions are made following conventional techniques of pharmaceutical technology involving mixing, filling, and dissolving the ingredients, as appropriate, to give the desire oral, parenteral, rectal, transdermal, or topical products (0151).
Regarding claim 24, Gudrun et al. teach physico-chemical characteristics of insulin glulisine-loaded protamine nanocapsules before and after freeze drying (See 0232). Blank and insulin glulisine-loaded protamine nanocapsules (1%w/v) were lyophilized in presence/absence of trehalose or sucrose at 5% (w/v). the freeze-dried formulations were resuspended with ultrapure water by manual resuspension and their physicochemical characteristics were evaluated (See 0256). The resuspended dispersions of blank and insulin glulisine-loaded protamine nanocapsules showed physicochemical properties, size and zeta potential, that were similar to those of the pre-freeze-dried systems (See 0272).
Regarding claim 26, Gudrun et al. teach Diabetes mellitus is a metabolic disorder in which the ability to use glucose is more or less completely lost. For decades, insulin has been used in the treatment of diabetes mellitus. Several insulin formulations have been developed, e.g., insulin zinc (II) suspension, formulations containing protamine, etc. Fast acting insulin preparations are usually solutions of insulin, while long-acting preparations can be suspensions containing insulin in crystalline and/or amorphous form precipitated by the addition of zinc salts (e.g., zinc chloride) alone or by addition of protamine or by a combination of both (See 0002).
Regarding claim 28, Gudrun et al. teach the term protamine refers to a mixture of strongly basic peptides which belongs to a family of natural arginine-rich polypeptides. It contains approximately 70% of L-arginine monomers and has a molecular weight of 4000-10000 Da. As protamine contains amino acids having free basic side chains, it has a certain buffering capacity and is therefore considered to be a buffering agent. Protamine has been approved by the regulatory authorities as a pharmaceutical excipient and nowadays its main application is in formulations for sustained release of insulin (See 0184). The invitro release studies were performed for PArg nanocapsules prepared with 20mM acetate buffer FaSSIF-V2 medium. The conclusion is that PArg nanocapsules provide a sustained release of the encapsulated insulin (See 0295).
Regarding claim 29, Gudrun et al. teach in order to control the pH of the nanoparticles suspending medium a number of buffers at different concentrations were explored. Acetate buffer was found to be appropriate in terms of preserving the physico-chemical properties and insulin loading of PArg nanocapsules. Physico-chemical properties of PArg NCs prepared with pH 5.5 acetate buffer at different concentrations. An additional requirement for PArg nanocapsules to be used for the oral administration of insulin was their colloidal stability. As shown in fig. 13, PArg NCs have good colloidal stability in simulated intestinal fluid (SIF, pH 6.8), fasted state SIF (FaSSIF-V2, pH 6.5) and fed state simulated intestinal fluid (FeSSIF-V2, pH 5.8, with enzyme) (See 0292, table 8, and 0294).
Regarding claim 30, Gudrun et al. teach insulins are administered parenterally, Non-invasive administration routes like oral delivery of insulin are investigated but there are several hurdles, as such enzymatic degradation in the gastrointestinal tract, drug efflux pumps, insufficient and variable absorption from the intestinal mucosa, as well as first pass metabolism in the liver (See 0003). Simulated intestinal fluid (SIF) pH 6.8 in the presence and absence of enzymes, fasted state, upper small intestine pH 6.5 and fed state, upper small intestine pH 5.8. (See 0251).
Regarding claim 31, Gudrun et al. teach as shown in table 8, a concentration 20 mM acetate buffer was found to be adequate for the preservation of the nanocapsules properties. The encapsulation efficiency for this formulation was 88±5%. Physico-chemical properties of PArg NCs prepared with pH 5.5 acetate buffer at different buffer concentrations (See 0292, and table 8). The insulin-loaded PArg NCs prepared 20mM acetate buffer were found to be stable at 20°C. for at least 45 days (fig. 12), while at 4°C. there is a tendency of aggregation after 1 week storage. Count rate in the figures indicate the concentration of the NCs (See 0293). The in vitro release studies were performed for PArg nanocapsules prepared with 20 mM acetate buffer FaSSIF-V2 medium. The results in fig 14, indicate that a 22% initial insulin release, followed by gradual release up to 54% until 4h. In fig. 13, it is also shown that amount of insulin that remains retained in the nanocapsules over the incubation time. By comparing the % of insulin released and that of insulin retained in the nanocapsules, it could be speculated that there is a partial degradation/aggregation of insulin once released to a FaSSIF-V2 from the nanocapsules (See 0295).
Regarding claims 11, and 36-38, Gudrun et al. teach according to the present invention the nanocapsule system, a mixture of surfactants, at least one surfactant, which is a bile salt and/or bile salt derivative selected from the group consisting of sodium cholate (HLB 18), sodium deoxycholate (HLB 16), sodium glycocholate (HLB16-18), sodium taurocholate (HLB 16) and sodium taurodeoxycholate (HLB 20.1) (See 0031). Human insulin was also encapsulated ibn protamine nanocapsules with an oleic acid oil core. The encapsulation values were dependent on the type of bile salt. Constant parameters, concentration in the final formulation (mg/ml): oleic acid=11.8; PEGst 40=2.4; protamine=1, (pH of final formulation 6-7) (See 0267 and Table 3c).
Response to Arguments
Applicant's arguments filed 05/13/2026 have been fully considered but they are not persuasive.
The applicant contends that neither Geschwind et al. nor Gudrun et al. teaches or suggests the presently claimed pharmaceutical composition, particularly an active pharmaceutical ingredient carrier ionic association complex comprising insulin and a bile salt, wherein the complex is encapsulated by hydroxypropyl β-cyclodextrin to form an inclusion complex. The applicant further argues that the office has failed to establish a prima facie case of obviousness because the references allegedly do not disclose every claimed element and do not sufficiently identify the differences between the prior art and the claimed invention.
These arguments are not persuasive because they address the references individually rather than considering the combined teachings upon which the rejection is based. A rejection under 35 U.S.C. 103 does not require that every claim limitation be expressly disclosed in a single reference. Rather, the relevant inquiry is whether the collective teachings of the cited references would have suggested the claimed subject matter to one of ordinary skill in the art at the time of the invention.
Geschwind et al. teaches pharmaceutically acceptable compositions comprising ionic association complexes formed between an active pharmaceutical ingredient and a carrier. Geschwind et al. further discloses that therapeutic agents may be formulated using encapsulating systems, including β-cyclodextrin, and explains that β-cyclodextrin forms inclusion complexes by surrounding guest molecules within its hydrophobic cavity to improve protection, stability, and delivery of pharmaceutical agents. Geschwind et al. additionally, teaches that active pharmaceutical ingredients may be formulated ad salts, microcapsules, liposomes, or other encapsulated forms, thereby recognizing beta-cyclodextrin as a suitable encapsulating material for pharmaceutical complexes.
However, Geschwind et al. does not specifically exemplify insulin in combination with a deoxycholate bile salt, the reference establishes the general concept of forming ionic association complexes between therapeutic agents and carriers and further teaches encapsulation of such pharmaceutical entities using β-cyclodextrin inclusion complexes. Therefore, Geschwind et al. provides the structural and functional teachings regarding ionic association complexes and β-cyclodextrin encapsulation relied upon in the rejection.
Gudrun et al. supplies the specific pharmaceutical components absent from Geschwind et al. Gudrun et al. teaches insulin formulations incorporating bile salts, including sodium deoxycholate, sodium cholate, and sodium glycocholate, as functional surfactants to improve delivery. Gudrun et al. further teaches encapsulating insulin-containing formulations within nanocapsule systems to protect insulin from enzymatic degradation and enhance absorption during-invasive administration. These disclosures demonstrate the recognized use of bile salts in association with insulin and the encapsulation of such formulations to improve pharmaceutical performance.
Accordingly, the rejection does not rely on Geschwind et al. alone to disclose insulin or bile salts. Rather, Geschwind et al. is relied upon for teaching ionic association complexes and β-cyclodextrin inclusion complex technology, while Gudrun et al. is relied upon for teaching insulin formulations incorporating bile salts and encapsulation strategies. The references are properly combined because each addresses the common objective of improving the stability, protection, and delivery of pharmaceutical agents through carrier-based formulations and encapsulation techniques.
The applicant’s assertion that Geschwind et al. fails to expressly disclose an insulin-bile salt ionic association complex is likewise unpersuasive because obviousness is not limited to the precise embodiments disclosed in the references. A reference need not describe the identical combination claimed where the modification represents the predictable use of prior art elements according to their established functions. One of ordinary skill in the art would have reasonably understood that the ionic association principles and β-cyclodextrin encapsulation taught by Geschwind et al. are applicable to the insulin-bile salt formulations disclosed by Gudrun et al., since both references employ conventional pharmaceutical carrier systems intended to stabilize and deliver therapeutic agents.
Therefore, the combination of Geschwind et al. and Gudrun et al. continues to teach or at least render obvious the claimed pharmaceutical composition comprising an active pharmaceutical ingredient carrier ionic association complex including insulin and a bile salt, wherein the complex is encapsulated by hydroxypropyl beta-cyclodextrin to form an inclusion complex. Accordingly, the rejection under 35 U.S.C. 103 is maintained.
In addition, while the invention is described as an ionic association complex, there is nothing in the instant specification or claims to indicate that anything was necessary beyond mixing the ingredients to achieve an ionic association complex. Therefore, when the deoxycholate salt and the bile salt are placed in proximity with each other they form an ionic association complex.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Barber whose telephone number is (703) 756-5302. The examiner can normally be reached on Monday through Friday from 6:30 AM to 3:30 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A. Wax, can be reached at telephone number (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY BARBER/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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