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 .
Claim Status
Claims 1-8 are pending. Applicant’s amendments have necessitated new grounds of rejection. Accordingly, this Action is FINAL.
Drawings
The drawings were received on 11/12/25. These drawings are acceptable.
Withdrawn rejections
Applicant's amendments and arguments filed 11/12/25 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn. Claim 8 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph and claims 7-8 were rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph. Applicant has amended the claims to overcome these rejections.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Zaman et al. (Pharmaceutics 2020, 12, 710; 25 pages) and Zhu et al. (Angew Chem Int Ed Engl. 2016 March 1; 55(10): 3309–3312) and Peppas et al. (European Journal of Pharmaceutical Sciences 2 9 (2006): 183–197) and Morcol et al. (International Journal of Pharmaceutics 277 (2004): 91–97) and Sonia et al. (Drug Discovery Today Volume 17, Numbers 13/14: July 2012).
Applicant claims, for example:
PNG
media_image1.png
552
864
media_image1.png
Greyscale
Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a pharmaceutical drug delivery research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from oral drug delivery systems, including insulin formulation and delivery, pharmaceutical formulation methods and techniques— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1 and 3, Zaman et al. teach that insulin is a fragile and sensitive peptide that shows extremely low bioavailability through the GI tract route of administration. Zaman et al. teach employing precipitated barium salt particles including BaSO4 loaded with insulin where the BaSO4 particles dramatically reduced hyperglycemia (Abstract), where the cations (Ba2+) and anions (SO42-) bind to insulin through electrostatic interactions (Page 3, 3rd paragraph). The particles were in the nanometer size range (Page 13, 3.3.2. Morphological Analysis of Ba Salt Particles by FE-SEM; Figure 7). Zaman et al. teach: “One of the biggest challenges in oral delivery is pre-systemic degradation due to harsh pH in the stomach having a fluctuating pH which can be extremely acidic (~pH 1) in fasting state. Therefore, any oral delivery agent needs to be resistant to extreme acidic pH to survive during GIT transport… Consistently high turbidity values for BaSO4 particles indicate their excellent resistance to degradation over a wide range of pHs at different time points” (Page 10, 3.2. Particle Stability Assessment). Thus, the insulin salts of Zaman et al. implicitly have both the cation-providing and anion-providing salts are present in the nano-precipitate at a sufficiently high concentration to enable adequate saturation of cationic and anionic salts, per volume of the nano-precipitate, such that the insulin is strongly bound therewith and buffered against premature release at an acidic pH.
Regarding claims 2 and 4-6, Zaman et al. teach methods of synthesis of the particles by precipitation reaction where: “Each type of Ba salt particle was prepared by incorporating a volume of cation- providing BaCl2 salt into either a volume of HEPES-buffered solution (pH adjusted to 8.0) or miliQH2O and mixing the solution with a volume of one anion-providing salt, Na2SO4, Na2SO3, and Na2CO3. Insulin was introduced right before addition of the 2nd salt to the medium.” Zaman et al. teach using 5 µL of 1 M BaCl2 and 2 µL of 1 M Na2SO4 which provides a ratio of 5:2. (Page 4, 2.2.1. Synthesis of Particles by Precipitation Reaction-2.2.2. Insulin Loading into Ba Salt Particles and Table 1). And schematically shown in Figure 2:
PNG
media_image2.png
422
638
media_image2.png
Greyscale
Consequently, Zaman et al. teach a method for producing the nano-precipitates by providing a volume of the cation providing inorganic metal salt (step i); add insulin to the cation metal salt (step ii) before adding the anion providing salt to the mixture (step iii) and mixing until a precipitate forms (step iv).
Regarding claim 7, Zaman et al. teach that insulin has been the one and only treatment for type 1 diabetes as well as for type 2 diabetes mellitus (Page 2 of 25, first paragraph), ostensibly in an animal or a human subject.
Regarding claims 1 and 4, Zhu et al. teaches that insulin has low permeability through the intestinal epithelium which makes oral absorption highly inefficient but that insulin nanoparticles surface coated with transferrin that can be effectively transported across the intestinal epithelium for oral insulin delivery where the transferrin enhances the transepithelial transport via transcytosis (Abstract) as shown in Figure 1a:
PNG
media_image3.png
426
1048
media_image3.png
Greyscale
Zhu et al. teach first mixing the insulin with polymer and the adding to the transferrin (Page 3, 3rd paragraph).
Regarding claims 1 and 4, Morcol et al. teach that insulin is sensitive to hydrolysis and enzymatic degradation (Page 92, left column 1st paragraph). To overcome that, Morcol et al. teach coating insulin particles with casein for oral delivery of insulin (Title; Abstract) where the insulin “particles are coated with casein, insulin will be protected in the acidic environment of the stomach when administered orally, and would be transported to the intestines where it would be absorbed into blood the stream.” (Page 92, right column 1st paragraph; Page 96, Conclusion). As shown in Figure 1:
PNG
media_image4.png
384
610
media_image4.png
Greyscale
Morcol et al. teach first making the insulin particles and then coating with casein (Page 92, 2.1. CAP-PEG-Ins (CAPI) particle preparation-Page 93, 2.3. Preparation of oral CAPIC (CAP-PEG-Ins-Cas)).
Regarding claims 1 and 4, Peppas et al. teach that an insulin-transferrin conjugate for oral administration to overcome not only the transport barrier in the small intestine but also the proteolytic attack during transit in the GI tract and across epithelial cells has been known since 2000 (Page 193, 3.6. Transferrin-mediated drug delivery).
Regarding claims 1 and 4, Sonia et al. teach that insulin casein is well-known to the artisan as a protein for oral insulin delivery (Abstract; Page 784, Insulin; Figure 2; Box 1, page 786; page 787, Casein). Sonia et al. also teach transcytosis as a mechanism for intestinal uptake of insulin (Page 785, left column 1st paragraph) and describe the attributes of an ideal oral insulin carrier (Page 785, Attributes of ideal oral insulin carrier).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
The difference between the instant application and Zaman et al. is that Zaman et al. do not expressly teach modifying the precipitated insulin-barium sulfate nanoparticles of Zaman et al. with only casein or transferrin. This deficiency in Zaman et al. is cured by the teachings of Zhu et al., Morcol et al., Peppas et al. and Sonia et al.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the precipitated insulin-barium sulfate nanoparticles of Zaman et al. with only casein or transferrin, as suggested by Zhu et al., Morcol et al., Peppas et al. and Sonia et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because for the following sound articulated reasoning with rational underpinning based upon the evidence. From the teachings of Zaman et al., it is apparent that the insulin in the nano-particulate salt complex is still exposed to the environment and could be subject to degradation as shown in Figure 2:
PNG
media_image5.png
190
242
media_image5.png
Greyscale
To overcome exposure of insulin to harsh pH environments as well as proteolytic enzymes, the combined references of Zhu et al., Morcol et al., Peppas et al. and Sonia et al. instruct the artisan to apply a coating of casein or transferrin where the transferrin has the added benefit of enhancing transcytosis as well. The ordinary artisan is motivated to do so to enhance the bioavailability of the insulin and would have a reasonable expectation of success in employing only casein and/or transferrin. Consequently, it is obvious to make the insulin barium sulfate salt complex of Zaman et al. and once the precipitate is formed then add a volume of only the bio-adhesive proteins casein or transferrin to the precipitate of step (iv) with a reasonable expectation of success. It then follows that such an insulin precipitate can be employed in methods of treatment of hyperglycemia, type 1 or type 2 diabetes mellitus to a human or animal subject in need thereof with a reasonable expectation of success.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Zaman et al. (Pharmaceutics 2020, 12, 710; 25 pages) and Zhu et al. (Angew Chem Int Ed Engl. 2016 March 1; 55(10): 3309–3312) and Peppas et al. (European Journal of Pharmaceutical Sciences 2 9 (2006): 183–197) and Morcol et al. (International Journal of Pharmaceutics 277 (2004): 91–97) and Sonia et al. (Drug Discovery Today Volume 17, Numbers 13/14: July 2012), as applied to claims 1-7 above, in further view of Caffrey (Baking Soda Could Prevent Infection for DKA Patients; [online] retrieved on 12/2/25 from: https://www.ajmc.com/view/baking-soda-could-prevent-infection-for-dka-patients; 2016; 6 pages).
Applicant claims:
PNG
media_image6.png
96
728
media_image6.png
Greyscale
The references of Zaman, Zhu, Peppas, Morcol and Sonia are discussed in detail above and those discussions are incorporated by reference.
Regarding claim 8, Caffrey teaches that a population of diabetic patients can avoid death from a fungal infection by administration of baking soda (sodium bicarbonate) (Page 1 of 6).
The combined references of Zaman, Zhu, Peppas, Morcol and Sonia do not expressly teach oral administration of bicarbonate before treatment with the insulin-loaded salt nano-precipitates. This deficiency in the combined references of Zaman, Zhu, Peppas, Morcol and Sonia is cured by the teachings of Caffrey.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to orally administer bicarbonate, as suggested by Caffrey, before treatment of hyperglycemic/type 1 or type 2 diabetic patients with the surface modified insulin-loaded salt nano-precipitates, as suggested by Zhu et al. as modified by Morcol et al., Peppas et al. and Sonia et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because it is desirable to avoid death by fungal infection in a population of diabetic patients simply by administration of baking soda. The oral administration route is an obvious choice by the artisan in this art. The timing of the administration before treatment with the insulin-loaded salt nano-precipitates surface modified with only transferrin or casein is also obvious given that there is no specified time period between administration times. The artisan can provide the oral sodium bicarbonate and then within 1 minute or 1 hour or 8 hours or 24 hours provide the insulin-loaded salt nano-precipitates surface modified with only transferrin or casein to have the bicarbonate administered before the insulin-loaded salt nano-precipitates surface modified with only transferrin or casein with a reasonable expectation of success. Consequently, oral administration of bicarbonate prior to administration of the insulin-loaded salt nano-precipitate surface modified with only transferrin or casein to treat hyperglycemia/type 1/type 2 diabetes is obvious over the combined references.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Response to Arguments: Applicant’s arguments filed on 11/12/25 have been carefully considered but are not persuasive. Applicant asserts that the insulin loaded salt nano-precipitate is surface-modified only with a bioadhesive protein selected from either transferrin or casein. Applicant argues that claim 1 is directed to a nanoparticles that is surface modified with transferrin after insulin loading and that Zhu and the state of the art teaches away. Respectfully, the Examiner has a different perspective. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). In the present case, the combined references teach and suggest a protein coating of either transferrin or casein on insulin particles provides a beneficial function as discussed above. That is not a teaching away.
Applicant asserts that “the salt nano-precipitate of amended claim 1 of the present application is surface modified without the use of any chemical linkers i.e. only with either transferrin or casein. For the invention of amended claim 1, the bio-adhesive
protein (transferrin or casein) is adsorbed on the surface of an insulin-loaded salt
precipitate and acts as a pH buffer to prevent premature release of insulin at acidic
pH.” (Page 7 of remarks). Respectfully, that is already known. The combined references teach the well-known acid sensitivity of insulin and suggest transferrin and casein to enhance the bioavailability of the insulin. Furthermore, the term “only” does not require exclusion of any linking agents but only limits the bio-adhesive protein to either transferrin or casein. The Examiner has met that limitation. Applicant’s arguments are not persuasive.
Applicant’s discussion of Morcol and Sonia is noted but the Examiner is relying upon those references as described in the rejection and not as characterized by Applicant.
On page 8 of remarks, Applicant directs the Examiner to Example 12 and Figures 27-29 for technical advantages. Respectfully, the Examiner has a different opinion. In Figure 27, there is essentially no difference between BaSO4-In and BaSO4-In-transferrin:
PNG
media_image7.png
398
646
media_image7.png
Greyscale
PNG
media_image8.png
462
748
media_image8.png
Greyscale
It is applicant’s burden to demonstrate unexpected results over the closest prior art. See MPEP 716.02, also 716.02 (a) - (g). Furthermore, the unexpected results should be demonstrated with evidence that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). In the present case, there does not appear to be a significant statistical difference between transferrin- (Figure 27) or casein- (Figure 28) modified BaSO4-insulin loaded precipitates and the BaSO4-insulin loaded precipitates as required to establish invention. Consequently, it is simply combination of known materials for their known properties that provides predictable results. “The combination of familiar elements [or steps] according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). A demonstration of mere improvement, without a showing that the improvement is significant or unexpected, is insufficient evidence of unexpected results. A showing of unexpected results requires Appellants to "demonstrate[] substantially improved results ... and state[] that the results were unexpected." In re Soni, 54 F.3d, 751(Fed. Cir. 1995). At best, Applicant characterizes the results as: “Surface modification of the BaSO4 particles with transferrin
helped sustained reduction of blood glucose levels, compared to unmodified BaSO4
particles”; and: “The result suggests that casein, when adsorbed on the surface of
the insulin-loaded nanoparticles, could play a positive role in further reducing blood
glucose levels” (Specification page 41, lines 5-7 and 18-20). Applicant did not characterize these results as unexpected or surprising. Applicant’s arguments are not persuasive. Consequently, the claims are obvious over the combined references without more.
MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after review of all the facts, Applicant’s arguments are not persuasive. The Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts, which is more convincing than the evidence which has been offered in opposition to it.
Conclusion
No claims are allowed.
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 ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Y Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERNST V ARNOLD/Primary Examiner, Art Unit 1613