DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Summary
Claims 1-20 are pending in this office action. All pending claims are under examination in this application.
Priority
The current application was filed on February 22, 2024. The current application claims domestic priority to provisional patent applications 63/495,472 and 63/486,296 filed April 11, 2023 and February 22, 2023, respectively.
Claim Objections
Claims 1-20 are objected to because of the following informalities:
Claims 1 and 10 should delete the text “…and a targeting molecule…” within the body of the claim in the second limitation. This phrase is repetitive with the third limitation. Or, the third limitation could be deleted, whichever is clearer.
Dependent claims 2-9 and 11-20 fail to cure the defects of claims 1 and 10, respectively.
Claims 2-6, 13-16, 18, and 20 have a colon after “wherein”. Please delete the colon.
Claims 6, 8-9, 18, and 20 has the general text “…is/at about X – about Y…”. Please amend this phrase to state “…is/at about X to about Y…”
Claims 2, 5-6, 9, 13, 16, and 18-19 contain acronyms (such as UiO-68-NH2 or PCN-222). Please define the acronym in full one time, and thereafter the abbreviation can be used within the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 is not clear to the reader whether the mass ratios described are experimental values to synthesize the MOF or post encapsulation. Therefore, it is unclear and indefinite. [For purposes of the rejection, the Examiner focused on the experimental ratios.]
Duplicate Claim Warnings
Applicant is advised that should claims 1 and 7 be found allowable, claim 10 and 19 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01 (m).
Furthermore, Applicant is advised that should claims 3 and 4 be found allowable, claim 14 and 15 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01 (m).
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 non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Farha et al. (US2021/0000924A1) in view of Kavimandan et al. (Bioconjugate Chemistry, 2006), Hwang et al. (KR20200099356A) and Yang et al. (CN114196034A).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Farha et al.
Farha et al. is considered the closest prior art to the present invention as it teaches insulin-loaded metal-organic frameworks (see title). In addition, Farha et al. disclose mesoporous zirconium metal-organic frameworks (MOFs) having insulin immobilized therein and methods of using the MOFs in insulin delivery are provided. The insulin-loaded metal-organic framework molecules include a porous zirconium metal-organic framework molecule and insulin molecules within pores of the porous zirconium metal-organic framework (see abstract).
2. Kavimandan et al.
Kavimandan et al. teach synthesis and characterization of insulin-transferrin conjugates (see title). Furthermore, Kavimandan et al. disclose that receptor-mediated endocytosis can be exploited for improving the transcellular delivery of therapeutic proteins. Insulin conjugated to transferrin by forming disulfide bonds has been shown to improve insulin oral bioavailability in diabetic rats. We are developing a combination strategy involving complexation hydrogels as delivery vehicles for insulin-transferrin conjugates. The complexation hydrogels developed in our laboratory have been shown to be promising carriers for oral delivery of proteins and peptides. Integrating the strategies based on the complexation hydrogels and insulin-transferrin conjugates may prove to be a novel approach for oral delivery of insulin and other therapeutic proteins. In this work, electrospray ionization mass spectrometry (ESI-MS) was used to study the modification of insulin during its reaction with transferrin. The stability of the conjugated insulin to enzymatic degradation was also studied. ESI-MS studies confirmed the site-specific modifications of insulin. The transferrin conjugation of insulin was also shown to increase the stability of insulin to enzymatic degradation (see abstract).
3. Hwang et al.
Hwang et al. teach MOF method for preparing hetero-metal ion-exchanged MOF and composition based on MOF for hetero-metal cation-exchange produced by post-synthetic modification used therein (see title). Additionally, Hwang et al. disclose that the present invention relates to a method for preparing a hetero-metal ion-exchanged MOF and an MOF-based composition for hetero-metal ion-exchange formed by post-synthetic modification by an organic compound used therein. The MOF of the present invention can be manufactured simply, and thus can replace conventional complex methods (see abstract).
4. Yang et al.
Yang et al. teach a preparation method, regeneration method and application of MOFs-NADH bionic reductase (see title). Also, Yang et al. disclose that the invention provides a preparation method, a regeneration method and application of MOFs-NADH bionic reductase, relates to the technical field of organic chemistry, can prepare and regenerate MOFs-NADH bionic reductase in a manual intervention mode, solves the problems that natural bionic reductase is not easy to obtain and high in cost, and is simple and convenient to operate in the preparation and regeneration process, high in yield, green and pollution-free. The method comprises the following steps: S1, synthesizing an MOF skeleton with free amino groups in N,N-dimethylformamide through a solvothermal method; S2, synthesizing an NADH (nicotinamide adenine dinucleotide) analogue of a 3-chloroformyl-1,4-dihydropyridine skeleton by using the MOF skeleton obtained in the S1; and S3, modifying and connecting the NADH analogue in the step S2 to the MOF skeleton by adopting a post-modification method, so as to obtain the porous MOFs-NADH bionic enzyme with the 3-carbamyl-1,4-dihydropyridine skeleton (see abstract).
Combination of Faeha et al. and Kavimadan et al.
Regarding instant claim 1, Farha et al. and Kavimandan et al. teach a composition comprising: a metal-organic framework (MOF) nanoparticle for oral protein administration. The necessary citations of Farha et al. and Kavimandan et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Farha et al. and Kavimandan et al. Citations
A composition comprising: a metal-organic framework (MOF) nanoparticle for oral protein administration,
Farha et al. disclose that the insulin-loaded metal-organic framework molecules include a porous zirconium metal-organic framework molecule and insulin molecules within pores of the porous zirconium metal-organic framework. The insulin-loaded metal-organic framework molecules can be delivered via oral administration to a patient (see paragraph [0007] within Farha et al.).
wherein the MOF comprises a nano-scale acid-resistant MOF; a small molecular protein/polypeptide drug and a targeting molecule,
Farha et al. disclose that mesoporous MOFs having insulin immobilized therein and methods of using the MOFs in insulin delivery are provided… The insulin-loaded MOFs are acid-stable and can prevent insulin from denaturing and degrading in the presence of stomach acid and/or in the presence of the digestive enzyme, pepsin (see paragraph [0028] within Farha et al.).
Additionally, Farha et al. disclose a MOF NP (MOF nanoparticle; see FIG. 13A within Farha et al.).
wherein the MOF is loaded with the small molecular protein/polypeptide; and targeting molecules,
Farha et al. disclose that in order to facilitate the internalization of the insulin-loaded MOFs by biological cells, the MOFs can be functionalized by oligonucleotides and, in particular, with terminal phosphate-modified DNA, to render them more colloidally stable in a physiological environment. This is illustrated in Example 3. By functionalizing the surfaces of insulin-loaded MOFs with oligonucleotides, cellular uptake can be increased, relative to the uptake of the native insulin, thereby providing a high payload with negligible cytotoxicity (see paragraph [0038] within Farha et al.).
Farha et al. does not disclose the addition of targeting molecules to the surface of the MOF. However, Kavimandan et al. discloses targeting molecules relevant to insulin that a skilled artisan (POSITA; person of ordinary skill in the art) would employ.
wherein a surface of the MOF is coated with the targeting molecules.
Kavimandan et al. disclose that an insulin-transferrin conjugate was synthesized by site specific modification of insulin and modification of transferrin by a heterobifunctional cross-linker. Proper modification of the insulin molecule, which is critical to its physiological function, was verified through fluorescence photometry and mass spectrometry. The conjugation resulted in a macromolecular heteroconjugate consisting of two insulin molecules and one transferrin molecule. Insulin in the conjugated form exhibited enhanced stability against proteolytic attack. The insulin transferrin conjugates synthesized here exhibit beneficial characteristics for oral delivery applications. This system when used in conjunction with the complexation hydrogels developed in our laboratory may result in a efficacious system for oral delivery of insulin (see page 1383, Conclusions; also see abstract; both within Kavimandan et al.).
Therefore, a skilled artisan (POSITA) would consult the disclosures of Farha et al. and Kavimandan et al. to teach all the elements of instant claim 1.
The remainder of the instant claims which are either directly or indirectly dependent on claim 1 are taught in full by the combination of Farha et al. and Kavimandan et al.
Regarding instant claims 3 and 14, Farha et al. and Kavimandan et al. teach wherein: the small molecular protein/polypeptide is a protein/polypeptide with a molecular weight less than or equal to about 10,000 Dalton and has therapeutic effect comprising salmon calcitonin, glucagon, interferon, or growth hormone. Farha et al. disclose an insulin-loaded MOF (see abstract within Farha et al.). Insulin has a molecular weight of ~5808 Daltons (see PTO-892 NPL 2U and 2V). A skilled artisan (POSITA) within the drug discovery realm would be able to identify drug candidates (having less than or equal to about 10,000 Dalton molecular weight) and targeting molecules that have therapeutic effects comprising salmon calcitonin, glucagon, interferon, or growth hormone.
Regarding instant claims 4 and 15, Farha et al. and Kavimandan et al. teach wherein the targeting molecules can target receptors on intestinal epithelial cell membranes, comprising transferrin, neonatal Fc receptor protein, cell penetrating peptide, octaarginine, or any combination thereof. Farha et al. disclose an insulin-loaded MOF (see abstract within Farha et al.). The disclosure of Kavimandan et al. supports the targeting of transferrin with insulin (see instant claim 1). Transferrin targets receptors on intestinal epithelial cell membranes (see PTO-892 NPL X).
Regarding instant claims 7-8 and 19, Farha et al. and Kavimandan et al. teach a method of preparing metal organic framework (MOF) nanoparticles for oral protein administration according to instant claim 1, the method comprising: adding the micromolecule protein/polypeptide or the solution thereof into the acid-resistant metal organic framework water solution; continuously stirring to ensure that the acid-resistant metal organic framework is coated with the micromolecule protein/polypeptide; and adding the targeting molecules or the solution thereof, and continuously stirring to ensure that the targeting molecule is adhered to the acid-resistant metal organic framework to obtain the metal organic framework nano-particle for oral protein administration. Please see the discussion and citations within instant claim 1. Farha et al. disclose an experimental procedure to prepare at room temperature their composition that is parallel to the instant claim 7 and 8 limitations (see paragraphs [0077] and [0079] within Farha et al.). [The full disclosure within Farha et al. encompasses all aspects of the procedure (see paragraphs [0072-0085] within Farha et al.).]
Regarding instant claim 10, Farha et al. and Kavimandan et al. teach a composition comprising: a metal-organic framework (MOF) nanoparticle for oral protein administration, wherein the MOF comprises a nano-scale acid-resistant MOF; a small molecular protein/polypeptide drug and a targeting molecule, wherein the MOF is loaded with the small molecular protein/polypeptide; and targeting molecules, wherein a surface of the MOF is coated with the targeting molecules. Please see the discussion and citations within instant claim 1 for the necessary rejection text.
Regarding instant claim 11, Farha et al. and Kavimandan et al. teach wherein the MOF nanoparticle comprises a conjugated mesoporous acid-resistant MOF. Please see the discussion and citations within instant claim 1 for the necessary rejection text.
Regarding instant claim 12, Farha et al. and Kavimandan et al. teach wherein the MOF comprises a Zr-MOF. Farha et al. disclose two mesoporous Zr MOFs (see paragraph [0024] within Farha et al.).
Regarding instant claim 20, Farha et al. and Kavimandan et al. teach wherein the preparation method is carried out at about 80 to about 130 °C. Please see the discussion and citations within instant claims 7-8 and 19 for the necessary rejection text. A skilled artisan (POSITA) would elevate the temperature and apply heat as needed to ensure complete conversion of the starting material to product.
Combination of Farha et al., Kavimandan et al., and Yang et al.
Regarding instant claim 2, Farha et al., Kavimandan et al., and Yang et al. teach wherein the MOF is UiO-68-NH2, PCN-222, PCN-224, or any combination thereof. Farha et al. disclose the MOF PCN-222 (see FIG.’s 8 and 13A within Farha et al.). Yang et al. disclose the MOF UiO-68-NH2 (see claim 2 within Yang et al.). Therefore, a skilled artisan (POSITA) could combine the two under routine experimental conditions.
Regarding instant claim 5, Farha et al., Kavimandan et al., and Yang et al. teach wherein the MOF is UiO-68-NH2, the small molecular protein/polypeptide is insulin, and the targeting molecules are transferrin. Yang et al. disclose the MOF UiO-68-NH2 (see claim 2 within Yang et al.). Farha et al. disclose an insulin-loaded MOF (see abstract within Farha et al.). The disclosure of Kavimandan et al. supports the targeting of transferrin with insulin (see instant claim 1). Therefore, a skilled artisan (POSITA) could combine the two references under routine experimental conditions to afford an insulin-loaded UiO-68-NH2 MOF.
Regarding instant claim 6, Farha et al., Kavimandan et al., and Yang et al. teach wherein: the MOF is UiO-68-NH2, the mass ratio of the insulin to the MOF is about 1:1 to about 1:6 UiO-68-NH2, and the mass ratio of the transferrin to the MOF is about 1:0.1 to about 1:1. Although Farha et al. does not disclose the use of the MOF, UiO-68-NH2, the procedures within that disclosure can apply to the instant claim 6 limitations.
Farha et al. disclose the maximum insulin loadings of 34 and 63 wt % were determined for NU-1000 and PCN-222 [post-encapsulation 0.34:1 (~2.9) or 0.63:1 (~1.6); see paragraph [0067] within Farha et al.]. Experimental insulin encapsulation follows the protocol outlined within paragraph [0077] of Farha et al. Based on the post-encapsulation numbers, excess insulin was used, specifically between 2.6 mg and 4.7 mg. 3 mg of MOF not conjugated to insulin was used as a reactant. Therefore, the experimental ratios are between 2.6 mg insulin:3 mg MOF to 4.7 mg insulin:3 mg MOF (overlapping ratios).
Farha et al. does not disclose using the targeting molecule transferrin. In an analogous manner, surface modification with terminal phosphate oligonucleotides (5’-(dGGT)10-phosphate-3’) employ a similar protocol. Farha et al. disclose that in a typical DNA functionalization experiment, excess phosphate terminated nucleic acid (100 nmol) was added to MOF NP colloids (~2 mg), and then left on a shaker to incubate for 4 hours (see paragraph [0079] within Farha et al.). Thus, this experimental could be applied to the targeting molecule transferrin. An excess amount of transferrin would fall within the range of 1:0.1 for the ratio of transferrin:MOF.
Combination of Farha et al., Kavimandan et al., and Hwang et al.
Regarding instant claim 13, Farha et al., Kavimandan et al., and Hwang et al. teach wherein the MOF is PCN-777. Hwang et al. disclose the MOF of PCN-777 (see claim 9 within Hwang et al.).
Regarding instant claims 16 and 17, Farha et al., Kavimandan et al., and Hwang et al. teach wherein the MOF is PCN-777, the small molecular protein/polypeptide is insulin, and the targeting molecules comprise a folate or folic acid. Hwang et al. disclose the MOF of PCN-777 (see claim 9 within Hwang et al.). Farha et al. and Kavimandan et al. disclose insulin-loaded MOFs (see instant claim 1). A skilled artisan (POSITA) would know the importance of the folate receptor within drug discovery (see PTO-892 NPL 2W). They would develop a drug candidate based on this receptor (folic acid or folate targeting molecules) through the combination of the three references.
Analogous Art
The Farha et al., Kavimandan et al., Hwang et al., and Yang et al. references are directed to the same field of endeavor as the instant claims, that is, a composition comprising: a metal-organic framework (MOF) nanoparticle for oral protein administration, disclosed within instant claim 1.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the insulin-loaded MOFs disclosed by Farha et al., using the teachings of Kavimandan et al. and further in light of the claim-specific features described in both Hwang et al. and Yang et al., in order to arrive at the subject matter of the instant claims.
The Farha et al., Kavimandan et al., Hwang et al., and Yang et al. references all have considerable overlap with the development of a target specific insulin-loaded MOF. In this instance, Farha et al. disclose insulin-loaded MOFs, while Kavimandan et al. supplies a biological target for insulin (transferrin), finally, both Hwang et al. and Yang et al. disclose claim-specific MOF examples. All references are directed to the development of a target specific insulin-loaded MOF and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to develop a target specific insulin-loaded MOF.
Starting with Farha et al., the skilled person only had to try the necessary claim limitations disclosed by Kavimandan et al., Hwang et al., and Yang et al. The combination of Farha et al., Kavimandan et al., Hwang et al., and Yang et al. would allow one to arrive at the present application without employing inventive skill. This combination of the insulin-loaded MOFs taught by Farha et al. along with the use of the necessary claim limitations taught by Kavimandan et al., Hwang et al., and Yang et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the insulin-loaded MOFs disclosed by Farha et al. with the use of the necessary claim limitations taught by Kavimandan et al., Hwang et al., and Yang et al. Incorporating the disclosure of Farha et al. into the target specific molecules presented by Kavimandan et al., followed by the additional MOF parameters disclosed by both Hwang et al., and Yang et al. represents a predictable use of prior art elements according to their established functions, consistent with MPEP §2143 and KSR.
Furthermore, the additional claim limitations taught by Kavimandan et al., Hwang et al., and Yang et al. would have been viewed by a POSITA as routine design optimizations or known modifications to develop a target specific insulin-loaded MOF. Implementing these features in Farha et al.’s insulin-loaded MOF would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Farha et al., supplemented by Kavimandan et al., Hwang et al., and Yang et al. provides all the elements of the claimed invention. The resulting target specific insulin-loaded MOF constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Allowable Subject Matter
Claims 9 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The subject matter of claims 9 and 18 have limitations that are not disclosed within the prior art. There is insufficient motivation to add these limitations to the closest reference of Farha et al.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615