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 .
The Applicants’ Amendment to the Claims filed on February 2, 2026 is entered.
Claims 1-35 are pending and under examination.
Election/Restrictions
Applicant's election with traverse of the species: “insulin peptides” for Species B from among the drug types listed in claims 10 and 27) in the reply filed on May 7, 2025 is as previously acknowledged. Further, applicants’ election for Species A being: “a multi-compartment dosage form” (for example see claim 28) and “combination that includes the antacid” and specifying that the embodiment of dosage form (vii) in claim 32, i.e., “a dosage form comprising a first part comprising an insulin peptide, sodium bicarbonate, mannitol and povidone K-30, and a second part comprising Labrasol, glycerol and water” in the reply filed on May 7, 2025 is as previously acknowledged.
However, upon further consideration, the species election requirement for Species A made in the Restriction mailed on May 7, 2025 was WITHDRAWN and species A were REJOINED and examined.
Priority
This US Application 17/719,969 filed on 04/13/2022 is a CON of 15/524,164 filed on 05/03/2017 (now US Patent 11,331,376) which is a 371 of PCT/IB2015/002181 filed on 11/04/2015 which claims US priority benefit of US Provisionals 62/197,286 filed on 07/27/2015 and 62/075,144 filed on 11/04/2014.
Terminal Disclaimer
The terminal disclaimer filed on February 2, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,331,376 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Response to Amendment
All objections and rejections made in the previous office action and not repeated in this office action are withdrawn in view of the Applicants’ Amendment to the Claims filed on February 2, 2026 and the Terminal Disclaimer filed for U.S. Patent No. 11,331,376.
Declaration of Yang
The Declaration of Yang under 37 CFR 1.132 filed on February 2, 2026 is insufficient to overcome the rejection of claims 1-35 based upon 35 U.S.C 103 as set forth in the last Office action because the Declaration is not commensurate with the scope of the presently claimed invention. Specifically, the Yang Declaration supports the argument of unexpected results for the embodiment of 200 IU/kg insulin in Formulation 1 (shown just below) suspended in a sodium bicarbonate (NaHCO3) antacid solution which exhibited the effects in decreasing blood glucose levels. Formulation 1 used for Example 6. Formulation 1 [0093]:
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However, none of the present claims recites such an embodiment. Present claims do not recite 200 IU/kg insulin in Formulation 1 with NaHCO3.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-35 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng et al. (US 7,018,980 B2; of record) in view of Gumkowski et al. (US 2003/0022944 A1, of record) and Bennis et al. (US 2009/0176691 A1, of record) as evidenced by Ma et al. (Acta Pharmacologica Sinica, 27: 2006: 1382-1388; IDS ref) and further in view of Bando et al. (US 2009/0175959 A1; of record).
Regarding base claims 1-2, 4, 8-9, 14, 15-16, 21, and 26-27, Zheng et al teach orally administered insulin oil (abstract). The composition comprises one or more liquid surfactants that have a HLB value of between 10 and 20 and one or more oils/hydrophobic emulsifiers that have a HLB value of between 0 and 10 and insulin that may be added thereto in the form of an aqueous buffered solution with a pH between 3 and 5 (abstract, col 1, In 55 to col 2, In 6). The liquid surfactant may be Tween 80 as well as polyethylene glycol-8-glycerol octanoate/decanoate and the oils/hydrophobic emulsifier may be polyglycerol-3-oleate or polyethylene glycol-6- glycerol monooleate, all of which are exemplified in Examples 1-3 (col 2, In 12-32, col 3, In 1-56). Ma et al evidences that the composition of Zheng is self-emulsifying and that such a emulsified composition demonstrates an average droplet size of 264.7 nm, which falls within the droplet size range set forth in claims 8-9 (Ma, pg 1384, col 2, para 5). Zheng et al teach that this insulin oil composition can be administered directly, enveloped into a capsule or mixed with pharmaceutically acceptable solid excipients to enable administration in a solid dosage form (col 2, In 40-45). Zheng et al. confirms that the insulin remains in the oil phase upon emulsification instead of the aqueous phase and thus the insulin resists degradation by digestive enzymes and is easily absorbed to bring about a favorable hypoglycemic effect (col 2, In 53-61).
Regarding claims 10-13, Zheng et al and Gumkowski et al explicitly teach human insulin peptide.
However, Zheng et al. teaches the oral insulin composition above, including providing a buffered solution of insulin, but fails to specifically teach the inclusion of antacid, such as sodium bicarbonate, the addition of a fumed silica nor suggests the combination of the PEG-8 caprylic/capric glycerides, propylene glycol monolaurate and polyoxyethylene (20) sorbitan monooleate in the same dosage form.
Regarding claims 1-3, 21, and 26, Bennis et al. teach inclusion of antacid.
Further, especially regarding claims 20-22, Gumkowski et al. teach self-microemulsifying compositions that comprise a poor oral bioavailiability active, such as a CETP inhibitor, a cosolvent, and like Zheng et al. teach a microemulsification system that comprises a surfactant having a low HLB value (i.e., 1-8) and a surfactant having an high HLB value (i.e., 8 to 20) and optionally a digestible oil (abstract). The combination of a high and low HLB surfactant results in a superior emulsification (para 0040). High HLB surfactants listed include TWEEN 80 and glyceryl PEG 8 caprylate/caprate which is referenced as LABRASOL (para 0043). Given the designation of LABRASOL as glyceryl PEG 8 caprylate/caprate, it is asserted that PEG-8 glyceryl caprylate/caprate and glyceryl PEG-8 caprylate/caprate reads on LABRASOL (i.e., PEG-8 caprylic/capric glycerides) cited by Applicants. Low HLB surfactants include propylene glycol monolaurate (i.e., LAUROGLYCOL FCC) as well as others, such as polyoxyethylene-6-apricot kernel oil, sorbitan esters of fatty acids and polyglyceryl oleate, which encompass species of low HLB surfactants taught by Zheng et al. (i.e., polyethylene glycol-6-glycerol monooleate/linoleate, Span 80 (sorbitan monoleate) and polyglycerol-3-oleate) (Gumkowski, para 0044).
Gumkowski et al specifically discloses TWEEN 80 and recites glyceryl PEG 8 caprylate/caprate and propylene glycol monolaurate among short lists of high and low HLB surfactants respectively from which it would have been easily envisaged to select them (para 0087). Gumkowski et al. further suggests that polyethylene glycols and 1,2 propylene glycol can be used as solvents for solvating the active in the composition (para 0042).
Bennis et al disclose a composition that comprises at least one protein active ingredient, such as human insulin that is sensitive to digestive enzymes and a buffering compound, such as anhydrous sodium bicarbonate (abstract, para 0001, 0069- 0072, claims 1 and 6). The amount of buffer is sufficient such that when the dosage form is in gastrointestinal environment the pH is between 4 and 8, such as 5-7 (para [0031]-[0036]). Bennis et al. teach that the composition may take a solid or liquid form, and the antacid/buffer and other components including the insulin active may be provided together as a simple mixture (i.e. homogenous composition) or in separate dosage forms to be administered jointly or quasi jointly such that the buffer effect develops during the passage of the active ingredient in the digestive tract (para [0021]- [0030], [0058]-[0061]). Bennis teach that the dosage form may take the form of an effervescent tablet and exemplifies such an effervescent tablet (a unitary dosage form) that contains sodium bicarbonate, monosodium citrate as well as human insulin and colloidal silica (adsorbant), which will facilitate fast dissolving of the tablet once ingested and exposed to gastric juices (para [0056]-[0057], claim 9). Bennis et al. further evidences that a buffered insulin tablet brought on a significant decrease in glycemia in 30 minutes and that the action was relatively short-lived, reducing to approximately less than 25% of maximal activity in 3 hours (Table 1, Batch 3, para [0092)).
Regarding claims 18, 21-22, and 31-32, Bennis et al. disclose a composition that comprises at least one protein active ingredient, such as human insulin that is sensitive to digestive enzymes and a buffering compound, such as anhydrous sodium bicarbonate (abstract, para 0001, 0069- 0072, claims 1 and 6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to provide a solid dosage form that contains a surfactant system that includes a non-ionic surfactant, such as the high HLB non-ionic surfactant PEG-8 glyceryl caprylate/caprate (i.e., LABRASOL) and the low HLB emulsifier polyglycerol-3-oleate as well as insulin that self-emulsifies upon contact with an aqueous medium under conditions of mild agitation as Zheng et al. exemplifies such a composition.
One of ordinary skill in the art would have been motivated to provide such a composition in order to provide insulin in such a way that it is protected from degradation from digestive enzymes and is easily absorbed, resulting in a favorable hypoglycemic effect. Regarding the specific combination of TWEEN 80, LABRASOL and LAUROGLYCOL FCC, such would have been obvious over the teachings of Zheng et al. which exemplifies use of TWEEN 80 and what is PEG-8 glyceryl caprylate/caprate (LABRASOL) in self-emulsifying insulin containing compositions and the teachings of Gumkowski et al. which recites TWEEN 80 and LABRASOL in a short list of high HLB surfactants and propylene glycol monooleate (IE LAUROGLYCOL FCC) in a short list of low HLB surfactant/emulsifiers for use in self-emulsifying compositions. As both Zheng et al. and Gumkowski both teach including low and high HLB surfactants in order to obtain superior self-microemulsifying compositions, and further list both low and high HLB surfactants which are the same or almost identical, one of ordinary skill in the art would have had a reasonable expectation of success in utilizing low and high HLB surfactants of Gumkowski in the composition of Zheng et al.
Furthermore, it would have been prima facie obvious to provide the combination of PEG-8 glyceryl caprylate/caprate and TWEEN 80 both known as high HLB surfactants and used for the same purpose in order to obtain a second combination with these same properties and usefulness. In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980).
Additionally, it would have been obvious to one of ordinary skill in the art to provide a propylene glycol or polyethylene glycol solvent as taught by Gumkowski et al. in order to enhance the solvation of the insulin in the composition. Additionally, as Gumkowski et al. teaches that the insulin is human insulin, it would have been obvious to utilize naturally-occurring or synthetic forms of human insulin in the composition of Zheng et al., especially in order to provide a composition that is more compatible with a human to which the composition may be administered.
Regarding inclusion of an antacid within the dosage form in solid or liquid form, such would have been obvious based upon the teachings of Bennis et al. which teach including an amount of antacid in liquid or solid form in an insulin containing composition sufficient to bring the gastrointestinal environment to a pH level of 4-8 upon administration of the insulin containing dosage form.
One of ordinary skill in the art would have been motivated to do so to provide an extra layer of defense against degradation of the insulin within the gastrointestinal tract before it can be absorbed and provide a hypoglycemic effect. One would have further have been motivated to do so in order to provide an effervescent composition, such as by the inclusion of the antacid sodium bicarbonate in order to buffer the pH of the stomach as well as provide an effervescent composition, if the composition is solid, which dissolves more quickly once administered to provide a faster hypoglycemic effect to a patient in need thereof. Additionally, it would have been obvious to one of ordinary skill in the art to provide a colloidal silica as exemplified in Bennis et al. in order to aid in formulating the solid composition.
Regarding claims 33-35, the ability of the dosage form to provide rapid onset of action, such as within 15-30 minutes as well as a short duration of action falling to less than 25% of maximal activity less than 5 hours following administration would have been obvious over the teachings of the cited prior art. Specifically, Bennis discloses administering buffered insulin tablets, where a significant reduction of glycemia is achieved after 30 minutes and demonstrate that the action is short lived, giving less than 25% effect after only 3 hours. When combined with the teachings of Zheng et al. regarding inclusion of insulin with a self-microemulsifying surfactant system which would further expedite the absorption of the insulin in the gastrointestinal tract, one would have expected an even faster onset of action of the insulin so delivered. Thus, these pharmacokinetic properties would have been obvious.
Regarding claims 28-30, the limitations regarding a unitary dosage form such as a tablet, which can be a substantially homogenous composition, such would have been obvious over the teachings of Zheng et al which teach mixing the ingredients with solid carriers to obtain a solid dosage form and the teachings of Bennis that teach providing a simple mixture (i.e., homogenous composition) of the insulin composition as a tablet (i.e., unitary dosage form).
Regarding claims 8-9, the average size of the droplets of the formed emulsion as well as the pH level the antacid provides upon ingestion, a prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05.
Especially regarding claims 3, 5-7, 23-25, and 28-30, regarding providing the composition in solid form, such as a simple mixture of all of the ingredients in liquid or solid form or providing the bolus of antacid separately from the rest in a different dosage form in a kit, as Bennis et al. teaches both a homogenous mixture of all the ingredients, including the insulin and antacid as well as providing the insulin separate from the insulin, both aspects would have been obvious to one of ordinary skill in the art. Furthermore, one of ordinary skill in the art would have known how to accomplish providing the insulin oil of Zheng et al. in a solid form because Zheng specifies how to accomplish this.
Regarding claim 21, Bennis et al. that disclose providing a kit that comprising a solid dosage of the insulin composition along with an amount of an aqueous solution to dissolve or suspend the antacid. Such would have been obvious over the disclosure wherein the insulin and antacid composition may be provided in liquid or solid form. An ordinarily skilled artisan would have been motivated to do so in order to administer the composition to a patient that has difficulty swallowing a pill and also to prevent any decomposition that may occur when the antacid and insulin are in contact together in liquid form.
Regarding claim 17, the requirement that the amount of antacid is sufficient to raise the gastric pH of the animal to at least about 3 within about one minute following ingestion of the dosage form, such would have been obvious over the liquid dosage form of Bennis et al. that has enough antacid to raise the pH up to approximately 8, which liquid would also provide immediate effect of the antacid.
Regarding the limitation of claim 19 that requires that the amount of antacid is sufficient to neutralize at least about 1 milliequivalent of stomach acid, as Bennis et al. envisions adjusting the pH of the amount of the entire stomach acid within the stomach to about 8, such a property would have necessarily have been present in the amount envisioned by Bennis et al.
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention because the prior art is suggestive of the claimed invention.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to provide a solid dosage form that contains a surfactant system that includes a non-ionic surfactant, such as the high HLB non-ionic surfactant PEG-8 glyceryl caprylate/caprate (IE LABRASOL) and the low HLB emulsifier polyglycerol-3-oleate as well as insulin that self-emulsifies upon contact with an aqueous medium under conditions of mild agitation as Zheng et al exemplifies such a composition.
One of ordinary skill in the art would have been motivated to provide such a composition in order to provide insulin in such a way that it is protected from degradation from digestive enzymes and is easily absorbed, resulting in a favorable hypoglycemic effect. Regarding the specific combination of TWEEN 80, LABRASOL and LAUROGLYCOL FCC, such would have been obvious over the teachings of Zheng et al. which exemplifies use of TWEEN 80 and what is PEG-8 glyceryl caprylate/caprate (_LABRASOL) in self-emulsifying insulin containing compositions and the teachings of Gumkowski et al. which recites TWEEN 80 and LABRASOL in a short list of high HLB surfactants and propylene glycol monooleate (IE LAUROGLYCOL FCC) in a short list of low HLB surfactant/emulsifiers for use in self-emulsifying compositions. Furthermore, it would have been prima facie obvious to provide the combination of PEG-8 glyceryl caprylate/caprate and TWEEN 80 both known as high HLB surfactants and used for the same purpose in order to obtain a second combination with these same properties and usefulness. In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980). Additionally, it would have been obvious to one of ordinary skill in the art to provide a propylene glycol or polyethylene glycol solvent as taught by Gumkowski et al. in order to enhance the solvation of the insulin in the composition. Additionally, as Gumkowski et al. teaches that the insulin is human insulin, it would have been obvious to utilize human insulin in the composition of Zheng et al., especially in order to provide a composition that is more compatible with a human to which the composition may be administered.
Regarding inclusion of a bolus of antacid within the dosage form, such would have been obvious based upon the teachings of Bennis et al. which teach including an amount of antacid in an insulin containing composition sufficient to bring the gastrointestinal environment to a pH level of 4-8 upon administration of the insulin containing dosage form.
One of ordinary skill in the art would have been motivated to do so to provide an extra layer of defense against degradation of the insulin within the gastrointestinal tract before it can be absorbed and provide a hypoglycemic effect. One would have further have been motivated to do so in order to provide an effervescent composition, such as by the inclusion of the antacid sodium bicarbonate in order to buffer the pH of the stomach as well as provide an effervescent composition which dissolves more quickly once administered to provide a faster hypoglycemic effect to a patient in need thereof. Regarding the average size of the droplets of the formed emulsion as well as the PH level the antacid provides upon ingestion, a prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05.
Especially regarding claims 3, 5-7, 23-25, and 28-30, Bennis et al. discloses providing the composition in solid form, such as a simple mixture of all of the ingredients or providing the bolus of antacid separately from the rest in a different dosage form in a kit. For example, Bennis et al. teaches both a homogenous mixture of all the ingredients, including the insulin and antacid as well as providing the insulin separate from the insulin, both aspects would have been obvious to one of ordinary skill in the art.
Furthermore, one of ordinary skill in the art would have known how to accomplish providing the insulin oil of Zheng et al. in a solid form because Zheng specifies how to accomplish this.
Regarding providing a kit that comprises a solid dosage of the insulin composition along with an amount of an aqueous solution to dissolve or suspend the antacid, such would have been obvious over the disclosure of Bennis et al. that disclose that the insulin and antacid composition may be provided in liquid or solid form.
An ordinarily skilled artisan would have been motivated to do so in order to administer the composition to a patient that has difficulty swallowing a pill and also to prevent any decomposition that may occur when the antacid and insulin are in contact together in liquid form.
Regarding the requirement that the amount of antacid is sufficient to raise the gastric pH of the animal to at least about 3 within about one minute following ingestion of the dosage form, such would have been obvious over the liquid dosage form of Bennis et al. that has enough antacid to raise the pH up to approximately 8, which liquid would also provide immediate effect of the antacid. Regarding the limitation of claim 19 that requires that the amount of antacid is sufficient to neutralize at least about 1 milliequivalent of stomach acid, as Bennis et al. envisions adjusting the pH of the amount of the entire stomach acid within the stomach to about 8, such a property would have necessarily have been present in the amount envisioned by Bennis et al.
Further, insofar as the cited references differ from the presently claimed invention regarding the alternative embodiment in the claims wherein the antacid is found in a different portion of the dosage form than the other components (for example, claims 5-7, 23, and 28, such as in a multi-compartment dosage form), Bando et al discloses such multi-compartment dosages.
Bando et al teach a dosage form that comprises an active ingredient that is sensitive to acid along with an antacid (abstract, para 0027, 0098). Bando et al teach core/shell tablets as well as bi-layer and multilayer tablets where the antacid is present as an outer layer over a sustained release part of an active ingredient as well as where the different aspects (i.e., antacid, immediate release, sustained release) form different parts/layers of the tablet (see para 0146).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zheng et al, Gumkowski et al, Bennis et al. and Bando et al. because all of these references are directed to dosage forms which contain actives which are sensitive to low pH and sensitive to enzymes active in this low pH. It would have been obvious to one of ordinary skill in the art to provide a dosage form where the antacid and active, such as insulin, are present at different parts of the dosage form based upon the teachings of Bando et al. Furthermore, based upon the teachings of Bando et al., it would have been obvious to provide a tablet wherein the antacid is provided as a coating or layer over an active containing core.
One of ordinary skill in the art would have been motivated to do so to ensure that the antacid is the first component to encounter the stomach acid in order to neutralize the acid before the active is released, thus inhibiting to a large degree degradation of the active due to exposure to low pH and enzyme active in low pH environments.
In view of the high skill in the art, it is considered that one of ordinary skill in the art having the cited references before the effective filing date would have had a reasonable expectation of success to arrive at a dosage form which contains an antacid, an active ingredient sensitive to acidic environments and a self-microemulsifying system.
In view of the high skill level in the art it is considered that one of ordinary skill in the art having the cited references before the effective filing date of the presently claimed invention would have had a reasonable expectation of success to combine the elements of the cited references as discussed in the body of the rejection above to arrive at the presently claimed invention.
Thus the claims as a whole are rendered obvious over the prior art.
Response to Arguments
The Applicants’ response filed on February 2, 2026 has been fully considered but is unpersuasive for reasons provided in the body of the rejection and provided here. The applicants argue:
The Examiner argues that Zheng, Gumkowski, and Bennis in combination would have rendered obvious the claimed dosage form. But there would have been no reason to modify Zheng with Bennis and/or Gumkowski in the manner suggested. Zheng discloses a method for preparation of an orally administrated insulin oil formulation by dissolving insulin in an acidic aqueous buffer. See Abstract. However, as conceded by the Examiner, Zheng does not disclose adding an antacid in preparing the insulin oil formulation. The Examiner applies Bennis and Gumkowski for allegedly disclosing these features. Bennis discloses a "buffer" system to prepare pharmaceutical compositions. See Abstract. As discussed in the attached Rule 132 Declaration, Bennis relates to pharmaceutical compositions containing at least one protein active ingredient protected from digestive enzymes. See 19. Bennis describes the pharmaceutical compositions containing the at least one protein active ingredient, in free form, as well as, for liquids, a system that buffers them to a pH greater than 4 and less than or equal to 8 or, for solids, a system that exerts, when they are placed in a liquid medium, a buffer effect between a pH greater than 4 and a pH less than or equal to 8.
The applicants argue that Bennis requires a “buffer” system to prepare the pharmaceutical composition, shown in Bennis Table B. The applicants argue:
Tablet B requires at least three components (1) anhydrous sodium bicarbonate, (2) anhydrous monosodium citrate and (3) monosodium phosphate, where (1) sodium bicarbonate acting as a weak base is paired with (2) monosodium citrate and (3) monosodium phosphate acting as acid/co-buffers, to establish the buffer system at pH 6.8. See Declaration at 19. In this regard, sodium bicarbonate itself is a mild base (around pH ~8.3) which cannot provide a condition of pH 6.8 unless paired with an acid partner such as citrate or phosphate. Id. Bennis teaches sodium bicarbonate together with its acid partners to establish the buffer system. Id. Bennis is silent with respect to removing the acid partners and selecting sodium bicarbonate only to oppositely reveal its mild-base function as an antiacid in order to raise the pH condition. Id.
In any event, a buffer system is completely different from an antiacid, as would be understood by one of ordinary skill in the art. See Declaration at 10. Although they are both pH-related, they are two different things. Id. In particular, a buffer system relies on a conjugate acid-base pair, which can be either a weak acid and its conjugate base, or a weak base and its conjugate acid, to keep pH. Id. This is not the same as "a weak base alone" acting as an "antiacid" to "change" pH. Id.
Bennis using a "buffer" system is irrelevant to the claimed dosage form that employs an antiacid in a dosage form. See Declaration at 10. A buffer system is primarily designed to "maintain" the pH stability of a formulation. Id. Through the combination of a weak acid and its conjugate base (or a weak base and its conjugate acid), it allows the formulation to "keep" pH at a nearly constant value during storage or use, ensuring the drug's chemical stability. Id.
On the other hand, an antiacid is an ingredient used to neutralize stomach acid for therapeutic effects. See Declaration at 10. It is typically a weak base that works by neutralizing the excess stomach acid (hydrochloric acid). Id. It is used to directly and substantially "change" the pH condition in the stomach. Formulation design focuses on its neutralizing capacity and onset of action instead of the stability of the formulation. Id. A comparison is given in the table below and copies of relevant information from wiki websites (Appendix I and Appendix II) are as attached as support. See Declaration at para 10.
Therefore, Bennis using a "buffer" system is irrelevant to the claimed dosage form that employs an "antiacid" in a dosage form. See Declaration at 10. One of ordinary skill in the art would not have considered Bennis or, in any event, would not have been motivated to select an antiacid in a dosage form based on Bennis's teachings to predictably arrive at the claimed dosage form. Id. In Zheng and Bennis, there is no teaching or suggestion to give up Bennis's buffer system, let alone replace Bennis's buffer system with a basic compound as an antiacid and even further to modify Zheng's composition to combine a SMEDDS with an antiacid to arrive at the claimed dosage form. Id. Thus, there would have been no reason to modify Zheng with Bennis to somehow predictably arrive at the claimed dosage form. Id.
The remaining applied references do not cure the deficiencies of Zheng and Bennis.
Gumkowski discloses self-emulsifying formulations of cholesteryl ester transfer protein (CETP) inhibitors, such as compounds of formula I to XIII. See Abstract. Ma describes a self- emulsifying formulation for oral delivery of insulin. See Abstract. Bando merely relates to a controlled release solid preparation of a proton pump inhibitor (PPI) represented by formula (1) containing an antacid. As discussed in the Declaration, Gumkowski and Bandon do not relate to a polypeptide drug, such as insulin. See 1111 and 12. And Gumkowski, Ma, and Bando do not contemplate a combination of a SMEDDS and an antiacid for a hydrophilic polypeptide drug such as insulin which achieves rapid onset and short duration of action. Id. As it relates to Ma, low glucose levels were maintained throughout the 24-h period (page 1386, right column, the paragraph "Oral efficacy of the formulation", Figure 5). This teaches away from the claimed dosage form which achieves a relatively short duration of action (falling to less than 25% of maximal activity less than 5 hours, and preferably less than about 4 hours, following administration for insulin, for example).
Thus, there would have been no reason to modify Zheng with Gumkowski and/or Bennis (or Ma and Bando) to somehow predictably arrive at the claimed dosage form that employs a combination of a SMEDDS and an antiacid for achieving rapid onset and short duration of action for a hydrophilic polypeptide drug such as insulin.
Moreover, the claimed dosage form produces unexpected results. As discussed in the attached Rule 132 Declaration, the claimed dosage form includes a combination of a self- microemulsifying drug delivery system (SMEDDS) and an antiacid, which provides rapid onset and short duration of action, for a hydrophilic polypeptide drug which is gastrically impractical, such as insulin. See Declaration at 14. As demonstrated in the Examples in the specification, the combination of a SMEDDS and an antiacid for a hydrophilic polypeptide drug such as insulin is required to achieve rapid onset and short duration of action, while an antiacid alone or SMEDDS only fail to achieve such effects. See Example 6, and Figure 1. These results show that only the third group (to which 200 IU/kg insulin in Formulation 1 suspended in a NaHCO₃ antacid solution) exhibited the effects in decreasing blood glucose level, while the first group (free insulin with a NaHCO₃ antacid solution) or the second group (Formulation 1 in PBS, SMEDDS only without antiacid) failed to achieve such effects. See Declaration at 15. The applied references do not disclose or even contemplate these unexpected results.
The applicants conclude that for “at least these reasons, the applied references would not have rendered obvious claims 1, 21, and 26” and continue that the “dependent claims are also allowable at least based on their dependence on an allowable base claim, as well as for the additional features recited therein.
However, the applicants’ argument that Bennis discloses a buffer rather than an antacid is unpersuasive because Bennis et al. teach inclusion of antacid. Bennis teach that the dosage form may take the form of an effervescent tablet and exemplifies such an effervescent tablet (a unitary dosage form) that contains sodium bicarbonate, monosodium citrate as well as human insulin and colloidal silica (adsorbant), which will facilitate fast dissolving of the tablet once ingested and exposed to gastric juices (para [0056]-[0057], claim 9). Bennis et al. disclose a composition that comprises at least one protein active ingredient, such as human insulin that is sensitive to digestive enzymes and a buffering compound, such as anhydrous sodium bicarbonate (abstract, para 0001, 0069- 0072, claims 1 and 6). Further, regarding the argument that the references fail to teach an antacid, Bando et al teach a dosage form that comprises an active ingredient that is sensitive to acid along with an antacid (abstract, para 0027, 0098). Bando et al teach core/shell tablets as well as bi-layer and multilayer tablets where the antacid is present as an outer layer over a sustained release part of an active ingredient as well as where the different aspects (i.e., antacid, immediate release, sustained release) form different parts/layers of the tablet (see para 0146).
Further, the applicant’s argument is unpersuasive that a reference teaches away from the claimed dosage form which achieves a relatively short duration of action (falling to less than 25% of maximal activity less than 5 hours, and preferably less than about 4 hours, following administration for insulin, for example). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971 ). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551,554, 31 USPQ2d 1130, 1132
(Fed. Cir. 1994).
Further, the applicants’ argument that there would have been no reason to modify Zheng with Gumkowski and/or Bennis (or Ma and Bando) to “somehow predictably arrive at the claimed dosage form that employs a combination of a SMEDDS and an antiacid for achieving rapid onset and short duration of action for a hydrophilic polypeptide drug such as insulin” is unpersuasive at least because the claims are drawn to a product rather than to a method and the limitations of achieving rapid onset and short duration are considered to be functional properties of claimed product. A product cannot be separated from its properties. MPEP 2112 states "Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable.
Further, the applicants’ arguments regarding unexpected results is not persuasive because the Yang Declaration supports the argument of unexpected results for the embodiment of 200 IU/kg insulin in Formulation 1 (shown just below) suspended in a sodium bicarbonate (NaHCO3) antacid solution which exhibited the effects in decreasing blood glucose levels. Formulation 1 used for Example 6. Formulation 1 [0093]:
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However, none of the present claims recites such an embodiment. Present claims do not recite 200 IU/kg insulin in Formulation 1 with NaHCO3.
Further, the applicants’ argument that there would be no motivation to combine the elements of the cited references, as stated in the body of the rejection above, one of ordinary skill in the art would have been motivated to provide such a composition in order to provide insulin in such a way that it is protected from degradation from digestive enzymes and is easily absorbed, resulting in a favorable hypoglycemic effect.
Allowable Subject Matter
The species of the surfactant system of PEG-8 caprylic/capric glycerides, propylene glycol monolaurate and polyoxyethylene (20) sorbitan monooleates at a ratio of 40: 3.3: 1 is allowable in the context of a self-emulsification composition that comprises the gastrically impractical drug insulin and an antacid sufficient to raise the gastric pH of the mammal to at least 3 upon ingestion of the dosage form.
Conclusion
No claim is allowed.
Relevant Prior art which may be applied in a future office action:
Hsu et al. (US 2010/0273730; of record);
Sharma et al “Antacid co-encapsulated polyester nanoparticles for peroral delivery of insulin: Development, pharmacokinetics, biodistribution and pharmacodynamics” International Journal of Pharmaceutics” 2013 Vol 440: pages 99-110; of record).
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.
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/ Primary Examiner, Art Unit 1658