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 .
Information Disclosure Statement
The information disclosure statement filed November 27, 2023 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. In this instance, while foreign document number CN115038441A has an associated section in English, this section is a duplicate of the statement of relevance for foreign document number CN112147117A and accordingly reads as a partial translation of foreign document number CN112147117A. Thus, this English section is not relevant to foreign document number CN115038441A and is not considered to be an appropriate concise explanation of relevance. The IDS has been placed in the application file, and references other than CN115038441A (which has been struck through) have been considered.
Drawings
The drawings are objected to for the following reasons.
The graph of Figure 7 provides a line graph comparing the absorbance properties of six samples. However, the colors of the curves are not sufficiently different so as a reader can readily assign the appropriate curve to the correct sample.
Appropriate correction is required.
Specification
The use of the terms CY5, QUANTA, JET BIOFIL, and ACTIVASE, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because of the following informalities:
On page 5, lines 6-13, there appears to be a run-on sentence that is not grammatically correct. It appears to be a sentence fragment ending with “providing a sufficient” followed by a complete sentence starting with “The expanded.” In its current state, this section is difficult to understand.
On page 5, lines 14-20, there appears to be a run-on sentence that is not grammatically correct. It appears to be a sentence fragment ending with “and rapidly” followed by a complete sentence starting with “Actual experiments.” In its current state, this section is difficult to understand.
On page 5, line 23, there is a period missing after the word “environments.”
On page 5, lines 25-30, there is a run-on sentence and improper capitalization of “Simple.” Please correct line 23 to instead include “and the operation is simple. Aqueous conditions” instead.
On page 5, line 31 through page 6, line 3, there appears to be a run-on sentence that is not grammatically correct. It appears to be a sentence fragment ending with “providing monitoring” followed by a complete sentence starting with “And to provide.” In its current state, this section is difficult to understand.
On page 7, line 14, the term “MOF” is recited, but no antecedent basis for this abbreviation is provided before this recitation. At the first use of an abbreviated phrase, provide the full original phrase meant by the abbreviation.
On page 7, lines 27-28, “the ligand solution uses distilled water or distilled water with dimethylformamide added as TCPE” has unclear meaning, as it could be construed to be redefining TCPE as water or water with DMF.
On page 10, line 16, the recitation of the sentence fragment “Measured on a meter.” Is superfluous and should be removed.
On page 11, line 26, the recitation of the sentence fragment “ability.” Is superfluous and should be removed.
On page 12, line 24, there is an improper period after the word “values.”
On page 13, line 29, the recitation of the sentence fragment “Cumulative release curve of tetracycline.” Is superfluous and should be removed.
On page 14, line 12, there appears to be improper punctuation and capitalization between sentences. Please revise to “…stability and biocompatibility. By loading…” instead.
Appropriate corrections are required.
Claim Objections
Claims 7, 13, 18, and 19 are objected to because of the following informalities:
Claim 7, step 5, recites “…precipitates at a bottom of the mixed solution is washed…” The word “is” should be replaced with “are” due to the plural noun “precipitates” or the phrase should be “the precipitate at the bottom of the mixed solution is washed.”
In claim 13, the phrase “wherein in step 4) the mixed solution into multiple experimental groups…” is unclear and appears to be missing one or more words between “solution” and “into.”
In claim 18, “comprising” is improperly conjugated. It should be revised to “comprises” instead.
In claim 19, “comprising” is improperly conjugated. It should be revised to “comprises” instead.
Appropriate correction is required.
Claim Interpretation
The examiner interprets the chemical formula for the manganese-based organic framework in claims 1 and 16, Mn2(TCPE)(H2O), to provide the accurate descriptive stoichiometry and compositional description of the claimed framework. In the absence of any compositional data to support stoichiometric ratios of individual components or the full elemental makeup, the provided formula is the only source of such information. Thus, it is understood that for every molecule of TCPE in the composition, there are two manganese ions and one water molecule. Furthermore, given the provided formula, it is understood that the water is coordinated to the manganese ion in the framework and is thus an integrated component of the lattice structure and not a guest molecule. If water was a guest molecule, the proper notation in the art would be [Mn2(TCPE)]·(H2O).
In claim 4, the term “gases” is interpreted to strictly encompass gases that are known to have use as drugs and not non-therapeutic gases, as “gases” is provided among a list of categories of drugs in a claim that narrows the recitation of “drugs” in claim 3, from which claim 4 depends.
In claim 4, the phrase “other drugs” is interpreted to encompass all drugs that are not anticoagulants, antiplatelets, anti-inflammatory drugs, gases, or anticancer drugs.
In claim 5, the phrase “wherein the gases include…” is interpreted to mean that the list of gases that the manganese-based organic framework is arranged to be used for loading comprises nitric oxide, hydrogen, hydrogen sulfide, and carbon monoxide, but is not limited to that list of gases.
In claim 6, the phrase “wherein the manganese-based organic framework is arranged to come in contact with a target object through patches, implants, bandages, stents, catheters, or other implantable or non-implantable devices,” is interpreted to mean that the manganese-based organic framework is incorporated into any of these devices by any means.
In claim 6, the phrase “for delivery, treatment, and/or diagnosis” is interpreted to be functional language. A composition is defined by its structure and not its intended use. Therefore, art that reads on the manganese-based organic framework being incorporated into the aforementioned devices such that it will come in contact with an object through the device reads on this claim regardless of the intended use of that art.
In claim 7, step 5 is interpreted to mean that the precipitate settles to the bottom of a container at any point after stirring the mixed solution for a designated time and before the precipitate is washed and centrifuged. The claims in view of the specification do not provide any additional requirements in the given description of “allowing it to settle.”
Claim 8 is interpreted to contain functional language. In claim 8, the phrase “for deprotonation” provides a desired function of the one or more base and does not recite a required procedural element of the claimed method.
In claim 9, the ratio range recited as 1:2~1:4 is interpreted as a range of ratios from 1:2 to 1:4.
In claim 19, step 2, the recitation of “different dialysis membranes” is interpreted to mean that the drug-loaded drug delivery material containing solution is separately injected into multiple distinct dialysis membranes.
In claim 19, step 3 describes immersing the membranes into containers containing solutions with different pH values. It is interpreted that “different pH values” refers to the pH value of the solutions into which the membranes are being immersed rather than a comparison of the pH value of the contents of the membranes and the solutions into which they will be immersed.
Claim Rejections - 35 USC § 112(b)
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.
Claims 2-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “nanoscale” in claim 2 is used by the claim to mean “50 nm - 20 µm,” while the accepted meaning is “1 nm - 100 nm” (IUPAC Gold Book). The term is indefinite because the specification does not clearly redefine the term. It is unclear what size range is being claimed. Therefore, claim 2 is rejected for indefiniteness. Claim 2 will be examined under the interpretation that the specified range of 50 nm – 20 µm is the claimed size range.
Claim 3 recites the limitation "nanoparticles" in line three. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether “nanoparticles” refer to the manganese-based organic framework or an additional material. This also renders the term “aggregates” at the end of the claim indefinite, as it is not clear if the drug is loaded between aggregates of manganese-based organic framework or aggregates of a separate nanoparticle. Furthermore, claims 4 and 5 are also rejected due to their dependence on claim 3. For the purpose of examination of this claim, “nanoparticles” is interpreted to refer to the manganese-based organic framework and “aggregates” is thus interpreted to mean aggregates of the manganese-based organic framework.
Claims 3 and 4 recite the limitation “wherein the manganese-based organic framework is arranged to…” To the examiner’s understanding, “arranged” may describe a structural modification, such as removal of guest molecules from MOF pores or covalent modifications to the MOF surface. Describing the MOF as being “arranged to load” or “arranged to be used for loading” could suggest that the MOF is in a state that is not yet loaded with anything. However, there is no provided description of a structural modification performed to “arrange” the claimed MOF for loading any cargo. Alternatively, “arranged” may instead refer to a procedural step such as placing the MOF in a setting for loading. Further alternatively, it is possible the applicant means that the manganese-based organic framework is already in a loaded state and means to claim a MOF that is loaded with a drug or specific classes of drugs. Therefore, the claims are indefinite, as it is not understood what limitation is required by the “arranged to” phrases. Furthermore, claim 5 is also rejected due to its dependence on claim 4. For the purpose of examination, the examiner will interpret the claims to mean a manganese-based organic framework that has been loaded with a drug (claim 3) or a specific class of drug (claim 4).
Regarding claims 7 and 16, the terms “predetermined” and “designated” are used in steps 1, 2, and 5 of the method of making the manganese-based organic framework. These terms render the claim indefinite because the bounds of what is meant by these terms is not made clear in the claims in view of the specification. Furthermore, claims 8-15 are also rejected due to their dependence on claim 7 and claims 17-20 are also rejected due to their dependence on claim 16. For the purpose of examination, “a predetermined amount of solvent” will be interpreted to mean any amount of solvent, “a predetermined amount of distilled water” will be interpreted to mean any amount of distilled water, and “stirring the mixed solution for a designated time” will be interpreted to mean stirring the solution for any amount of time.
Claim 7 recites the limitation "the mixed solution" in line 2 of step 5. There is insufficient antecedent basis for this limitation in the claim. Claims 8-15 are also rejected due to their dependence on claim 7.
Claim 7, step 5, recites “…allowing [the mixed solution] to settle, then precipitates at a bottom…” which is unclear in meaning and therefore indefinite. Furthermore, claims 8-15 are also rejected due to their dependence on claim 7.
Claim 9 recites “the deprotonated solution” in line 16 of page 2 of the claims. There is insufficient antecedent basis for this limitation in the claim. For the purpose of examination, the “deprotonated solution” will be interpreted to refer to the solution comprising the base required by claim 8.
Regarding claim 9, the limitation “wherein the deprotonated solution to the ligand solution is of a ratio in the range of 1:2~1:4” is unclear in meaning and therefore renders the claim indefinite. It is not understood what feature of these solutions is described by the provided range of ratios or what values are to be used to calculate the ratio. For the purpose of examination, this will be interpreted to describe a volume to volume ratio between the solution comprising the base required by claim 8 (see interpretation in the immediately above paragraph) to the solution comprising the TCPE ligand.
Regarding claim 10, the phrase “solvent content” in the context of the claim is not defined in the specification and is not used in the manner of a standard phrase in the art. Thus, it is unclear what is meant by this phrase, rendering the claim indefinite. For the purpose of examination, “solvent content” will be interpreted to mean the fractional content of organic solvents (such as dimethylformamide) in the otherwise aqueous solution.
Regarding claim 10, the ratio or value 1/4 is indefinite as the units and method of determining this value are not clear. It is unclear what values are to be used to calculate the radio. For the purpose of examination, the ratio is interpreted to refer to a volume to volume ratio of organic solvent to water (see interpretation in the immediately above paragraph).
Regarding claims 6 and 18, the term “target” is used. This term renders the claims indefinite because the bounds of what is meant by the term is not made clear in the claims in view of the specification and would not be obvious to a person having ordinary skill in the art. For the purpose of examination, “target object” will be interpreted to mean any object and “target drug” will be interpreted to mean any drug.
Regarding claim 18, the terms “adequate” and “predetermined” are used. These terms render the claim indefinite because the bounds of what is meant by these terms is not made clear in the claims in view of the specification and would not be obvious to a person having ordinary skill in the art. For the purpose of examination, “adequate solution” will be interpreted as any solution capable of use for suspending a drug and “predetermined ratio” will be interpreted to mean any ratio.
Regarding claim 19, the terms “adequate” and “predetermined” are used. These terms render the claim indefinite because the bounds of what is meant by these terms is not made clear in the claims in view of the specification and would not be obvious to a person having ordinary skill in the art. For the purpose of examination, “adequate solution” will be interpreted as any solution capable of use for suspending the drug-loaded delivery material and “predetermined temperature” will be interpreted to mean any temperature.
Regarding claim 19, it is unclear what is meant by “keeping the containers at a constant speed on a shaker.” There appears to be a verb missing between “containers” and “at.” Thus, the claim is considered by the examiner to be indefinite or failing to particularly point out the invention. For the purpose of examination, the claim is interpreted to mean that containers are placed on a shaker and the containers and shaken at a constant speed.
Claim 20 is rejected as being indefinite due to a lack of clarity regarding the meaning of the phrase “loading efficiency.” The phrase “loading efficiency” in claim 20 is used by the claim to mean the parameter value which is calculated by the following equation in which MT is defined as the total amount of target drug used and MuT is the unloaded amount of the target drug:
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100
However, the conventional meaning in the art is that which is calculated by the next equation:
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100
Thus, the used meaning of “loading efficiency” is contrary to its ordinary meaning in the art. The pair of the phrase “loading efficiency” and the provided equation used together as claimed would not be clear to a person of ordinary skill in the art as it is unclear which is the required element of the claim. While theoretically, different equations can be used to calculate the same parameter, in this instance, the claimed equation and the accepted equation in the art have significantly different ranges of output values and interpretations.
In the art of drug-loaded MOFs, loading efficiency is a parameter used to determine the efficacy of encapsulating or loading a drug within a MOF. The concept can be best described as determining what fraction of the initially provided starting drug material was effectively loaded into the MOF. Thus, the conventional equation in the art produces loading efficiency values from 0% at no loaded drug (MT = MuT) to 100% at fully loaded drug (MuT = 0). This range of values is reasonable for an assessment of how effectively a drug was loaded into a MOF.
If instead the equation is used as claimed, when no drug is loaded (MT = MuT), the calculated value is still 0%. However, under the condition of MuT = 0 and all drug is loaded, the value cannot be determined as it requires dividing by zero (and as a mathematical limit, as MuT approaches zero, the calculated loading efficiency value using the claimed equation approaches infinity). Furthermore, when MuT is equal to half the value of MT, the calculated loading efficiency value would be 100% despite the ordinary conceptual understanding that this is equivalent to half the drug being loaded (so 50% loading efficiency would be expected, which would be the value if the conventional equation in the art was used). Likewise, if more than 50% of the total input drug material is loaded into the MOF, this calculation of loading efficiency would produce values greater than 100% (eventually approaching infinity), which does not conceptually make sense for this system and experiment.
Claim 20 is thus indefinite because it is unclear whether the claimed method requires calculating the loading efficiency (as an understood term in the art) or by performing the calculation using the provided equation. Claim 20 will be examined under the interpretation that loading efficiency is the desired parameter to be determined and the examiner will interpret loading efficiency to mean that which is calculated by the provided accepted equation in the art, with MT in the denominator.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4 and 5 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 4, the scope of “for loading anticoagulants, antiplatelets, anti-inflammatory drugs, gases, anticancer drugs, and other drugs” is understood to encompass drugs that are anticoagulants, antiplatelets, anti-inflammatory drugs, gases, and anticancer drugs and all drugs that do not belong to the specified list (see Claim Interpretation). Therefore, this limitation fails to limit the subject matter of claim 3, upon which claim 4 depends. Claim 3 requires the manganese-based organic framework be arranged for loading drugs and claim 4 does not properly narrow the scope of the drugs for which the framework is arranged for loading.
Regarding claim 5, the scope of “the gases include nitric oxide, hydrogen, hydrogen sulfide, and carbon monoxide” is understood to not limit the scope of the claimed gases to only nitric oxide, hydrogen, hydrogen sulfide, and carbon monoxide (see claim interpretation). Therefore, this limitation fails to limit the subject matter of claim 4, upon which claim 5 depends. Claim 4 requires the manganese-based organic framework to be arranged for loading drugs that are gases and claim 5 does not properly narrow the scope of the gases for which the framework is arranged for loading.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
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.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Sun (Sun, F.Z.; et al., ACS Appl. Mater. Interfaces, 2020) in view of Wen (Wen, L.; et al., Chem. Commun., 2012) and Zhou (Zhou, C.C.; et al., Dalton Trans., 2021).
Sun teaches a manganese-based organic framework of formula Mn2(TCPE)(H2O)(DMF) (pg. 6106, last paragraph). The formula provides the stoichiometric ratios of the components of the composition: for every molecule of TCPE, there are two manganese ions, one manganese-coordinated water, and one manganese-coordinated DMF.
Sun does not teach a manganese-based organic framework of the formula Mn2(TCPE)(H2O).
Wen teaches a method of single-crystal to single-crystal transformations in metal-organic frameworks in which metal coordinating DMF molecules are replaced by water molecules (pg. 2846, Abstract). Wen teaches that this conversion was done by incubating the DMF-coordinating MOF in dichloromethane for 8 hours at room temperature (pg. 2846, last paragraph). Wen further teaches that this single-crystal to single-crystal transformation resulted in increased nitrogen and hydrogen gas adsorption properties (pg. 2848, Fig. 3) and increased framework stability and surface area (pg. 2848, second paragraph).
Zhou teaches a method of single-crystal to single-crystal transformations in a manganese-containing metal-organic framework. After creating a manganese-containing MOF in which seven water molecules were coordinated for every three manganese ions, further heating and extending the reaction time enabled the removal of coordinated water molecules, generating species with six or two water molecules for every three manganese ions (pg. 11084, Fig. 5). Zhou teaches that reducing the number of manganese-coordinated water molecules increases MOF thermal stability (pg. 11084, Fig. 7) and enables tailoring interlayer distance and porosity (pg. 11084, first paragraph).
A person of ordinary skill in the art would have recognized that the manganese-based organic framework of Sun, Mn2(TCPE)(H2O)(DMF), could be transformed by the manganese-based organic framework of the claimed formula, Mn2(TCPE)(H2O), as single-crystal to single-crystal transformations are standard procedures in the art of MOF synthesis. Furthermore, the single-crystal to single-crystal transformations taught by Wen and Zhou would have been recognized as specific route to obtaining the claimed structural formula. The improvement in gas adsorption, surface area, and thermal stability would provide a motivation for combining these methods.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the manganese-based organic framework of Sun, Mn2(TCPE)(H2O)(DMF), by incorporating the teachings of Wen (to swap the manganese-coordinated DMF with water) and Zhou (to reduce the number of coordinated water molecules, as such transformations could tailor the framework’s ability to adsorb gases, alter its porosity, and improve its stability. This would result in the predictable stepwise conversion of Mn2(TCPE)(H2O)(DMF) to Mn2(TCPE)(H2O)2 to Mn2(TCPE)(H2O), resulting in the claimed framework formula. Therefore, the combined teachings of Sun, Wen, and Zhou render claim 1 obvious.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, and Zhou as applied to claim 1 above, and further in view of Wang (Wang, L.; et al., J. Mater. Chem. B, 2016).
As described above, Sun, Wen, and Zhou combine to teach the creation of a manganese-containing organic framework of the formula Mn2(TCPE)(H2O).
These references do not teach a MOF in a size range of 50 nm – 20µm.
Wang teaches a metal-organic framework comprising TCPE (pg. 4263, Scheme 1). The MOF is prepared at multiple sizes by varying with the amount of acetic acid added during the synthesis (pg. 4264, paragraph 2). NCP-1-150 is an embodiment presented to have an average diameter of about 70 nm (pg. 4264, paragraph 2). Wang also teaches that when these particles have a diameter under 200 nm, they are able to participate in cell uptake (pg. 4264, paragraph 2).
A person of ordinary skill in the art would have recognized that the method of Wang, adjusting reaction components such as acetic acid during TCPE MOF synthesis, enables tailoring the size of a MOF to a desired size range. This known technique for MOF synthesis could readily be applied to improve the claimed MOF in the same way.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the manganese-based organic framework (taught by the combination of Sun, Wen, and Zhou) with the teaching of Wang to produce a manganese-based organic framework in a size range of 70 nm. Such size modulation would enable generating a claimed MOF capable of cellular uptake, which could improve drug delivery capabilities. Therefore, the combined teachings of Sun, Wen, Zhou, and Wang render claim 2 obvious.
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, and Zhou as applied to claim 1 above, and further in view of Zhu (Zhu, Z.H.; et al., Adv. Funct. Mater., 2021) as evidenced by Ding (Ding, H.; et al., Adv. Healthcare Mater., 2022).
As described above, Sun, Wen, and Zhou combine to teach the creation of a manganese-containing organic framework of the formula Mn2(TCPE)(H2O).
These combined teachings do not teach arranging the manganese-based organic framework to be loaded with drugs, including gases that are drugs.
Zhu teaches a metal-organic framework comprising TCPE (pg. 2, Section 2.1). The MOF is demonstrated to bind to hydrogen sulfide (pg. 6, first paragraph). Zhu demonstrates that hydrogen sulfide binding to the TCPE MOF does not significantly reduce or shift the fluorescence properties of the MOF (pg. 6, first paragraph and Fig. S20).
As evidenced by Ding, hydrogen sulfide has therapeutic applications (pg. 8, Section 4). Thus, hydrogen sulfide could be considered a gas that is a drug. This is in agreement with the teachings of the specification of the instant application, listing hydrogen sulfide among the list of gases that are interpreted to be drugs (pg. 2, line 29 and Claim Interpretation).
A person of ordinary skill in the art would have recognized that the method of Zhu, fumigating the TCPE MOF with hydrogen sulfide to bind the gas to the MOF, would generate a hydrogen sulfide-loaded MOF. This known technique for loading a MOF with a gas could readily be applied to improve the claimed MOF in the same way for these applications. It would also be recognized that hydrogen sulfide can serve as a drug.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the manganese-based organic framework (taught by the combination of Sun, Wen, and Zhou) with the teaching of Zhu to load the claimed manganese-based organic framework with hydrogen sulfide. Such incorporation would enable utilization of the claimed MOF for drug delivery functions, providing a therapeutic use to the composition, as evidenced by Ding. Therefore, the combined teachings of Sun, Wen, Zhou, and Zhu render claims 3-5 obvious.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, and Zhou as applied to claim 1 above, and further in view of Yin (Yin, M.; et al., ACS Nano, 2021).
As described above, Sun, Wen, and Zhou combine to teach the creation of a manganese-containing organic framework of the formula Mn2(TCPE)(H2O).
These combined teachings do not teach arranging the manganese-based organic framework to come into contact with a target object through patches, implants, bandages, stents, catheters, or other implantable or non-implantable devices for delivery, treatment, and/or diagnosis.
Yin teaches a metal-organic framework incorporated in a microneedle patch (pg. 17843, Scheme 1). The MOF is loaded into a needle tip microcavity of the microneedle patch mold.
A person of ordinary skill in the art would have recognized that the method of Yin, incorporating the MOF in the microneedle patch, enables utilization of the properties of the MOF at a desired tissue location. This known technique for MOF incorporation into a patch could readily be applied to improve the claimed MOF in the same way for these applications.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the manganese-based organic framework (taught by the combination of Sun, Wen, and Zhou) with the teaching of Yin to produce a microneedle patch that incorporates the claimed MOF. Such incorporation would enable targeted utilization of the claimed MOF for functions such as localized drug delivery. Therefore, the combined teachings of Sun, Wen, Zhou, and Yin render claim 6 obvious.
Claims 7-13 are rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, and Zhou as applied to claim 1 above, and in further view of Devi (Devi, Y.; et al., J. Mater. Sci., 2020).
As described above, Sun, Wen, and Zhou combine to teach the creation of and methods of making a manganese-containing organic framework of the formula Mn2(TCPE)(H2O). More specifically, the method of Sun includes adding a manganese precursor to a solvent, diluting TCPE in a solvent, and washing a precipitate (pg. 1606, Synthesis of NUM-7). Additionally, the method of Zhou includes adding a manganese precursor to a solvent, stirring a mixture of manganese and organic ligand, and washing a precipitate (pg. 11078, Section 2.1).
These combined teachings do not teach preparing separate manganese and TCPE solutions, deprotonating the TCPE solution, slowly adding the deprotonated TCPE solution to the manganese solution, or using centrifugation to isolate the product.
Devi teaches a method of making a metal-organic framework using iron and benzene-1,3,5-tricarboxylic acid (BTC) that includes preparing separate metal and organic ligand solutions, deprotonating the organic ligand, slowly combining the metal and organic ligand solutions, and using centrifugation to isolate the product (pg. 13787, Synthesis of Fe-MIL100). Furthermore, Devi teaches that the aqueous synthesis method used (along with the usage of sodium hydroxide to deprotonate the BTC solution) is a sustainable and biocompatible process (pg. 13786, paragraph 2).
A person of ordinary skill in the art would have recognized that Sun, Wen, Zhou, and Devi all teach methods of preparing MOFs. For the reasons described above, it would have been obvious to modify the method of Sun with those of Wen and Zhou. It would also be recognized that the MOF of Devi comprises similar components to the MOF of claim 1. Iron is a transition metal adjacent to manganese on the periodic table and the BTC organic ligand is similar to TCPE in that it comprises multiple carboxylic acid groups for the coordination of the metal in the MOF structure. The method of Devi is a known improved synthesis and isolation technique has been applied to MOFs before and could similarly be applied to the manganese-based organic framework taught though the combination of Sun, Wen, and Zhou in the same way, improving the sustainability of the method of making and the biocompatibility of the product.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of making the manganese-based organic framework taught by the combination of Sun, Wen, and Zhou with the teaching of Devi to prepare separate ligand and metal solutions, deprotonate the ligand before gradual combination with the metal solution, and centrifuging the product. This would make the synthesis more sustainable and the immediate product more biocompatible, which would make it easier to use the product for biomedical applications such as drug delivery.
Regarding claim 7, Sun teaches adding a manganese precursor (MnCl2·4H2O) to a solvent (a mixture of DMF, acetonitrile, and deionized water), diluting TCPE in the same solvent, and washing the yellow crystal product precipitate (pg. 6106, Synthesis of NUM-7). Zhou teaches adding a manganese precursor (Mn(CH3COO)2·4H2O) to a solvent (a mixture of DMF and water), diluting an organic ligand in the same solvent, stirring the mixture for 20 minutes, and washing the crystal product precipitate (pg. 11078, Section 2.1). Devi teaches adding a metal ion precursor (FeSO4·7H2O) to a solvent (deionized water), diluting the BTC organic ligand in an aqueous sodium hydroxide solution (which deprotonates the BTC ligand), gradually adding the iron solution to the deprotonated BTC solution, stirring the mixture, settling the precipitate at a bottom of a container via centrifugation, washing the product, and drying the product in a vacuum oven (pg. 13787, Synthesis of Fe-MIL100). Devi uses deionized water, of which distilled water is an obvious interchangeable variant in the art.
While Devi adds the metal solution to the deprotonated ligand solution, reversing the steps to add the ligand to the metal would be an obvious variant of the method and would be routine optimization of such a procedure. Similarly, Devi adds the base to a solution of water before adding the organic ligand; however, reversing these steps would similarly be routine optimization of such a procedure. The order of addition for this step is not expected to alter the results of the method. The two aforementioned modifications amount to a rearrangement of steps. Here, the order of steps does not impact the subsequent independent and distinct steps of claim 7 and yields the same results of deprotonated ligand and MOF product. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See MPEP § 2144.04(IV)(C).
The combination of the aforementioned methods of the provided references reads on the entirety of the limitations of the method of claim 7. Therefore, the combined teachings of Sun, Wen, Zhou, and Devi render claim 7 obvious.
Regarding claim 8, Devi used sodium hydroxide, a common base, for deprotonating the ligand solution (pg. 13787, Synthesis of Fe-MIL100). Therefore, the combined teachings of Sun, Wen, Zhou, and Devi render claim 8 obvious.
Regarding claim 9, although Devi does not expressly teach a specific ratio of ligand solution and base-containing solution to combine for preparing the deprotonated ligand, the selection of ratios such as those between 1:2 and 1:4 would be routine optimization equivalent to adjusting the concentration of the base. Devi teaches using a base to deprotonate the ligand to improve the method of synthesis of a MOF. The use of the base is to deprotonate the organic ligand to make it negatively charged prior to combining it with the positively charged metal ion. Altering the ratio of base solution to add to the ligand solution would enable the optimization of the deprotonation of the ligand. Therefore, the combined teachings of Sun, Wen, Zhou, and Devi render claim 9 obvious.
Regarding claim 10, Devi teaches a method of preparing a MOF in which the organic ligand is prepared in an aqueous sodium hydroxide solution (pg. 13787, Synthesis of Fe-MIL100). As this solution is free of organic solvent, the ratio volumes of organic solvent to water does not exceed 1/4 and therefore reads on this claim. Therefore, the combined teachings of Sun, Wen, Zhou, and Devi render claim 10 obvious.
Regarding claim 11, Devi stirs the mixture of metal ion and organic ligand at 30°C (pg. 13787, Synthesis of Fe-MIL100). Therefore, the combined teachings of Sun, Wen, Zhou, and Devi render claim 11 obvious.
Regarding claim 12, Devi stirs the mixture of metal ion and organic ligand for 24 hours (pg. 13787, Synthesis of Fe-MIL100). Therefore, the combined teachings of Sun, Wen, Zhou, and Devi render claim 12 obvious.
Regarding claim 13, although Devi does not expressly teach splitting a mixed solution into multiple experimental groups for stirring according to different temperatures, such a method step is considered routine optimization. Devi teaches stirring the mixture at 30°C (pg. 13787, Synthesis of Fe-MIL100). Generally, differences in temperature do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such temperature is critical (MPEP § 2144.05). Therefore, stirring the solution at another temperature in addition to the 30°C reaction would amount to routine optimization. As the claim is drawn toward a method of making a manganese-based organic framework of the formula Mn2(TCPE)(H2O), it is interpreted that both “experimental groups” stirred at “different temperatures” would produce a manganese-based organic framework of the formula Mn2(TCPE)(H2O). Thus, the splitting of the reaction mixture for stirring at different temperatures is not considered to be critical to the method of preparing the claimed manganese-based organic framework. Therefore, the combined teachings of Sun, Wen, Zhou, and Devi render claim 13 obvious.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, Zhou, and Devi as applied to claims 7-13 above, and in further view of Folling (Folling, J.; et al., Small, 2008) as evidenced by Demchenko (Demchenko, A.P., Methods Appl. Fluoresc., 2020).
As described above, Sun, Wen, Zhou and Devi combine to teach a method of making a manganese-containing organic framework of the formula Mn2(TCPE)(H2O). More specifically, the method of Sun includes adding a manganese precursor to a solvent, diluting TCPE in a solvent, and washing a precipitate (pg. 1606, Synthesis of NUM-7). Additionally, the method of Zhou includes adding a manganese precursor to a solvent, stirring a mixture of manganese and organic ligand, and washing a precipitate (pg. 11078, Section 2.1). Furthermore, Devi teaches a method of making a metal-organic framework that includes preparing separate metal and organic ligand solutions, deprotonating the organic ligand, slowly combining the metal and organic ligand solutions, and using centrifugation to isolate the product (pg. 13787, Synthesis of Fe-MIL100).
These combined teachings do not teach a method of preparing a manganese-based organic framework in which the MOF is allowed to settle in the dark.
Folling teaches a method of preparing a nanoparticle comprising an organic fluorescent dye using dark conditions (pg. 141, Synthesis of Fluorescent Nanoparticles). Although not expressly taught by Folling, it is understood in the art that limiting the exposure of organic fluorescent dyes from light decreases fluorophore degradation, as evidenced by Demchenko.
Demchenko teaches that light-induced degradation of organic fluorescent dyes can produce toxic materials (pg. 2, paragraph 1). Thus, limiting the exposure of organic fluorescent dyes to light decreases toxic degradation products.
A person of ordinary skill in the art would have recognized that Sun, Wen, Zhou, Devi, and Folling all teach methods of preparing nanomaterials. For the reasons described above, it would have been obvious to combine the methods of Sun, Wen, Zhou, and Devi. It would also be recognized that Sun, Devi, and Folling all describe methods of preparing nanoparticles comprising organic fluorescent dyes. The method of Folling of preparing a fluorescent material in the dark is known to decrease organic dye photodegradation, as evidenced by Demchenko. This known technique would readily improve the combined method of Sun, Wen, Zhou, and Devi in the same way.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of making the manganese-based organic framework taught by the combination of Sun, Wen, Zhou, and Devi with the teaching of Folling to prepare the manganese-based organic framework in the dark. This would decrease the light-induced degradation of the fluorescent TCPE ligand, limiting the formation of toxic byproducts, as evidenced by Demchenko, which would make the resulting product more biocompatible, making it easier to use the product for biomedical applications such as drug delivery. Therefore, the combined teachings of Sun, Wen, Zhou, Devi, and Folling render claim 14 obvious.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, Zhou, and Devi as applied to claims 7-13 above, and in further view of Balasubramanian (Balasubramanian, S.K.; et al., Biomaterials, 2010).
As described above, Sun, Wen, Zhou and Devi combine to teach a method of making a manganese-containing organic framework of the formula Mn2(TCPE)(H2O). More specifically, the method of Sun includes adding a manganese precursor to a solvent, diluting TCPE in a solvent, and washing a precipitate (pg. 1606, Synthesis of NUM-7). Additionally, the method of Zhou includes adding a manganese precursor to a solvent, stirring a mixture of manganese and organic ligand, and washing a precipitate (pg. 11078, Section 2.1). Furthermore, Devi teaches a method of making a metal-organic framework that includes preparing separate metal and organic ligand solutions, deprotonating the organic ligand, slowly combining the metal and organic ligand solutions, and using centrifugation to isolate the product (pg. 13787, Synthesis of Fe-MIL100).
These combined teachings do not teach a method of preparing a manganese-based organic framework in which the reaction mixture is centrifuged multiple times to obtain the product.
Balasubramanian teaches a method of preparing a nanoparticle. The method of purifying the nanoparticle after synthesis involves two centrifugation steps (pg. 9025, Section 2.2). Balasubramanian teaches that this technique of centrifuging the nanoparticles to purify them maximizes the recovery of the desired product and minimizes the amount of undesirable impurities obtained in the final product (pg. 9025, Section 2.2).
A person of ordinary skill in the art would have recognized that Sun, Wen, Zhou, Devi, and Balasubramanian all teach methods of preparing nanomaterials. For the reasons described above, it would have been obvious to combine the methods of Sun, Wen, Zhou, and Devi. It would also be recognized that both Devi and Balasubramanian teach purifying the nanomaterial from the crude reaction mixture via centrifugation. It would have been recognized that the method of multiple centrifugation steps of Balasubramanian increases the yield and purity of the nanomaterial product.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of making the manganese-based organic framework taught by the combination of Sun, Wen, Zhou, and Devi with the teaching of Balasubramanian to purify the manganese-based organic framework using multiple centrifugation steps. This would lead to the predictable result of increased yield and purity of the desired manganese-based organic framework product. Therefore, the combined teachings of Sun, Wen, Zhou, Devi, and Balasubramanian render claim 15 obvious.
Claims 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, and Zhou as applied to claim 1 above, and in further view of Cui (Cui, R.; et al., Inorganic Chemistry, 2021).
As described above, Sun, Wen, and Zhou combine to teach the creation of a manganese-containing organic framework of the formula Mn2(TCPE)(H2O).
These combined teachings do not teach using the manganese-based organic framework as a drug delivery material.
Cui teaches using a metal-organic framework as a drug delivery material (pg. 1664, Abstract). In this method, the MOF is loaded with the drug 5-fluorouracil (5-FU) by combining the MOF and drug in a solution, stirring for 24 hours, and centrifuging the suspension to isolate the drug-loaded MOF (pg. 1666, Section 2.3).
A person of ordinary skill in the art would have recognized that the method of Cui, using a MOF to load and release a drug, enables the utilization of a MOF as a drug delivery material, which could result in new pharmaceutical uses for the MOF. The work of Cui suggests that MOF materials can be effective drug delivery systems.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the manganese-based organic framework (taught by the combination of Sun, Wen, and Zhou) with the teaching of Cui to use the MOF as a drug delivery material. This would enable utilization of the MOF for drug loading and release.
Regarding claim 16, the combined teachings of Sun, Wen, and Zhou teach a manganese-based organic framework of the formula Mn2(TCPE)(H2O) (described above). Furthermore, Cui teaches a method of using a metal-organic framework as a drug delivery material (pg. 1666, Sections 2.3 and 2.4).
Regarding claim 17, Cui teaches a method of using a metal-organic framework for drug loading (pg. 1666, Section 2.3) and drug release (pg. 1666, Section 2.4).
Regarding claim 18, Cui teaches a method of using a metal-organic framework for drug loading comprising suspending a drug (5-FU) in water, adding the metal-organic framework to the drug solution at a 1:1 ratio (mass of MOF to mass of drug), stirring the suspension for 24 hours, and centrifuging the suspension multiple times (pg. 1666, Section 2.3). While Cui does not explicitly state that centrifugation occurs until the supernatant “becomes clear,” Cui teaches that washing and centrifugation is repeated “until the supernatant solution exhibited no signal of 5-FU” (pg. 1666, Section 2.3), which would result in a clear supernatant, as the 5-FU-free wash supernatant would be just water, which is clear.
Therefore, the combined teachings of Sun, Wen, Zhou, and Cui render claims 16-18 obvious.
Claims 16, 17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, and Zhou as applied to claim 1 above, and in further view of Zhang (Zhang, Y; et al., Inorg. Chim. Acta, 2018).
As described above, Sun, Wen, and Zhou combine to teach the creation of a manganese-containing organic framework of the formula Mn2(TCPE)(H2O).
These combined teachings do not teach using the manganese-based organic framework as a drug delivery material.
Zhang teaches using a metal-organic framework as a drug delivery material (pg. 8, Title). In this method, the MOF is loaded with the drug 5-FU, and the drug release process comprises transferring the drug-loaded MOF to dialysis bags, placing the filled dialysis bags in phosphate buffer solutions with different pH values, and shaking the containers at 60 rpm and with the temperature set to 37°C (pg. 9-10, Section 2.6).
A person of ordinary skill in the art would have recognized that the method of Zhang, using a MOF to load and release a drug, enables the utilization of a MOF as a drug delivery material, which could result in new pharmaceutical uses for the MOF. The work of Zhang suggests that MOF materials can be effective drug delivery systems.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the manganese-based organic framework (taught by the combination of Sun, Wen, and Zhou) with the teaching of Zhang to use the MOF as a drug delivery material. This would enable utilization of the MOF for drug loading and release.
Regarding claim 16, the combined teachings of Sun, Wen, and Zhou teach a manganese-based organic framework of the formula Mn2(TCPE)(H2O). Furthermore, Zhang teaches a method of using a metal-organic framework as a drug delivery material (pg. 8, Title).
Regarding claim 17, Zhang teaches a method of using a metal-organic framework for drug loading (pg. 9, Section 2.4) and drug release (pg. 9-10, Section 2.6).
Regarding claim 18, Zhang teaches a method of using a metal-organic framework for drug release comprising suspending the 5-FU loaded zinc MOF in a solution, placing the drug-loaded MOF in dialysis bags, immersing the dialysis bags in phosphate buffered saline solutions of pH 7.4 and pH 6.0, incubating the samples at 37°C and shaking the containers at 60 rpm (pg. 9-10, Section 2.6). While Zhang does not explicitly teach that the drug-loaded MOF was injected into the dialysis bags, transferring the drug-loaded MOF material into dialysis bags by injecting is an obvious variant of common techniques used to transfer materials into dialysis vessels, including pipetting and pouring. Performing any of these obvious variant steps is standard in the art and would result in the same effect of transferring the drug-loaded MOF into the dialysis bag. Injecting the sample is not expected to particularly produce any unexpected results.
Therefore, the combined teachings of Sun, Wen, Zhou, and Zhang render claims 16, 17, and 19 obvious.
Claims 16, 17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Sun, Wen, and Zhou as applied to claim 1 above, and in further view of Karami (Karami, A.; et al., Colloids Surf. B, 2022).
As described above, Sun, Wen, and Zhou combine to teach the creation of a manganese-containing organic framework of the formula Mn2(TCPE)(H2O).
These combined teachings do not teach using the manganese-based organic framework as a drug delivery material.
Karami teaches using a metal-organic framework as a drug delivery material (pg. 1, Abstract). In this method, the MOF is loaded with doxorubicin and loading capacity and loading efficiency parameters are calculated (pg. 2, Section 2.4).
A person of ordinary skill in the art would have recognized that the method of Karami, using a MOF to load and release a drug, enables the utilization of a MOF as a drug delivery material, which could result in new pharmaceutical uses for the MOF.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the manganese-based organic framework (taught by the combination of Sun, Wen, and Zhou) with the teaching of Karami to use the MOF as a drug delivery material. This would enable utilization of the MOF for drug loading and release.
Regarding claim 16, the combined teachings of Sun, Wen, and Zhou teach a manganese-based organic framework of the formula Mn2(TCPE)(H2O). Furthermore, Karami teaches a method of using a metal-organic framework as a drug delivery material (pg. 1, Abstract).
Regarding claim 17, Karami teaches a method of using a metal-organic framework for drug loading (pg. 2, Section 2.4) and drug release (pg. 3, Section 2.7).
Regarding claim 20, Karami teaches a method of using a metal-organic framework for drug loading comprising calculating encapsulation capacity and encapsulation efficiency (pg. 2, section 2.4), which correspond to the claimed parameters of loading capacity and loading efficiency, respectively.
With regard to the equation for encapsulation/loading capacity, Karami teaches the following equation:
E
n
c
a
p
s
u
l
a
t
i
o
n
C
a
p
a
c
i
t
y
=
m
l
o
a
d
e
d
m
l
o
a
d
e
d
+
m
M
O
F
×
100
where mloaded is the mass of encapsulated drug (which is mathematically equivalent to the difference between the total and unloaded amounts of drug, “MT-MuT”) and mMOF is the mass of the MOF material (which is equivalent to MC). Thus, the calculation of encapsulation capacity of Karami (pg. 2, Equation 2) reads on the claimed formula for calculating loading capacity.
With regard to the equation for encapsulation/loading efficiency, Karami teaches the following equation:
E
n
c
a
p
s
u
l
a
t
i
o
n
e
f
f
i
c
i
e
n
c
y
=
A
i
-
A
f
A
i
×
100
where Ai is the initial absorbance value, corresponding to the concentration of drug in solution prior to adding the MOF material and Af is the final absorbance value corresponding to the concentration of drug in the supernatant after the first centrifugation after mixing the drug and MOF material. Using a combination of Beer’s Law (A=εlc), the fact that concentration is equivalent to a molar amount divided by volume, and the fact that the volume of the solution for each absorbance measurement was equal, the absorbance portion of the above encapsulation efficiency equation can be converted to the following:
A
i
-
A
f
A
i
=
ε
l
c
i
-
ε
l
c
f
ε
l
c
i
=
ε
l
ε
l
×
c
i
-
c
f
c
i
=
c
i
-
c
f
c
i
=
m
o
l
i
V
-
m
o
l
f
V
m
o
l
i
V
=
V
V
×
m
o
l
i
-
m
o
l
f
m
o
l
i
=
m
o
l
i
-
m
o
l
f
m
o
l
i
=
m
o
l
i
-
m
o
l
f
m
o
l
i
×
m
d
r
u
g
m
o
l
d
r
u
g
m
d
r
u
g
m
o
l
d
r
u
g
=
m
d
r
u
g
i
-
m
d
r
u
g
f
m
d
r
u
g
i
where mdrug,i is the initial mass of drug present before adding the MOF material (which is equivalent to the total amount of drug used, MT) and mdrug,f is the mass of the drug in the supernatant (which is equivalent to the amount of drug not loaded into the MOF, MuT). Thus, the calculation of encapsulation efficiency of Karami (pg. 2, Equation 1) reads on the claimed formula for calculating loading efficiency (see claim interpretation at the end of the claim 20 112(b) rejection above).
Therefore, the combined teachings of Wen, Sun, Zhou, and Karami render claims 16, 17, and 20 obvious.
Conclusion
All pending claims are rejected.
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/E.P.M./ Examiner, Art Unit 1612
/SAHANA S KAUP/ Supervisory Primary Examiner, Art Unit 1612