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 .
Response to Amendment
The Amendment filed 10/15/2025 has been entered. Applicant’s amendments are in response to in the Non-Final Office Action mailed 07/15/2025. Applicant’s claims have been amended in the following manner: independent claim 1 has been modified via inclusion of “particle” and “one or more” to prompt a new ground of rejection, however the thrust of the current rejection remains essentially the same as before. New claims 41-42 have been entered to draw a new ground of rejection. Claim 10 is cancelled. The following objections/rejections are withdrawn: 112b rejection for claims 8 and 10 (due to amendments made).
The Examiner further acknowledges the following:
Claims 1-4, 7-8, 12-13, 15-19, 22, 26-27, 30, 34, 36, and 41-42 are pending.
Claims 27, 30, 34, and 36 are withdrawn from consideration as directed to non-elected inventions.
Claims 1-4, 7-8, 12-13, 15-19, 22, 26, and 41-42 are presented for examination and rejected as set forth below.
Claim Objections
Claims 17-19 recites the limitation "pharmaceutically acceptable polymer" as referred back to claim 1, which has now been amended to incorporate the term “particle”. Alignment of terminology is suggested.
New Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 8, 16-19, 22, 26, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Theranostics 2019, published 5/18/2019), as evidenced by Chemistry Views (2013), and in further view of Lin (US20160346204A1), Manoukian (J. Appl. Polym. Sci., 2018), and Gao (Scientific Reports, 2016).
Applicant’s claims are directed to a pharmaceutical composition (instant claim 1) comprising a therapeutic agent, a metal-organic frameworks (MOF) or coordination polymer, a pharmaceutically acceptable polymer, wherein the therapeutic agent is encapsulated. The “derived from” phrase in claim 12 is interpreted to mean that the therapeutic agent ‘originates from’ bacteria, protozoa, or microbes in a very general sense. In order to understand the amendment incorporation of “polymer particle” into instant claim 1c, for example, the Examiner turns to the specification for an example, and notes that these particles can be made with materials such as PLGA or PCL to encapsulate the MOF and/or therapeutic agent (pg 48-49 of Applicant’s Specification).
Liu teaches MOFs for nanomedicine, such that MOF particles are nanocarriers for drug delivery for improved biostability, biocompatibility, and targeted delivery (abstract), allowing for a wide range of therapeutic agents, including dyes, small molecules, and proteins with tuning of the pore size (pg 3122, paragraph 1). MOFs are compared to other drug delivery systems and formulations such that a person skilled in the art would apply typical formulation techniques in combination with MOFs (pg 3123, paragraph 4).
Regarding claim 1-4, 8 and 41: Liu teaches the polypeptide insulin encapsulated (reads on encapsulated therapeutic agent, as required by claim 1, and also reads on protein, as required by claim 41) by porous MOF NU-1000 (pg 3125, figure 2). Liu states that surface engineering of MOFs is commonly performed to improve performance, and for example, PEGylation is typically performed (pg 3128). Liu teaches use of Zn, Zr, and Fe to make MOF nanoparticles (pg 3129, paragraph 4), and a MOF framework steps from coordination of building units of metal ions and organic linkers (pg 3123, paragraph 2). Liu teaches ZIF-8 (pg 3125, paragraph 2), which is demonstrated as a suitable MOF in Applicant’s specification (Example 3). It is known in the art that a MOF is a subclass of a coordination polymer (specified in instant claim 3), as evidenced by Chemistry Views.
Regarding claim 16: Liu teaches immunotherapy (pg 3128, paragraph 2).
In summary (as discussed above), Liu teaches a composition comprising a therapeutic agent and a MOF for the purpose of drug delivery, especially with controlled release. However, Liu does not teach the pharmaceutically acceptable polymer of the formulation (instant claims 1, 17-19 and 22) or administration by injection (instant claim 26).
Lin teaches drug-loaded MOF formulations where the MOF can be administered by injection [0219-0226], and can include conventional formulation ingredients and strategies for drug delivery [0220-221]. Lin is interested in controlled release of the payload [0200]. Lin also teaches hydrophilic and organic polymers (such as polyesters) as coating agents or layers covering the metal-organic matrix material core (reads on “further encapsulated”…by a polymer) [0143-0146, 0185] (Lin – claim 17).
Manoukian teaches controlled release of drug formulations by using polycaprolactone (PCL), polylactic acid (PLA), copolymers such as PLGA, or combinations thereof (reads on polymers of instant claims 1, 17-19, and 22), where polymer selection, size, and shapes of injectable hydrogels (reads on instant claim 26) depend on target application (pg 2-3, introduction). Manoukian teaches several microsphere (reads on the newly amended term “particle” of instant claim 1) formulations have been explored for delivering drugs and release profiles were altered by changing particle size and drug content in the formulation (pg 3, paragraph 1).
Gao provides an example of a drug-loaded ZIF-8 MOF that is encapsulated into polymer layers (reads on “further encapsulated” …by a polymer) to generate an advanced drug delivery system with sustained drug release behavior (abstract).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Liu to formulate the MOFs with an injectable formulation, using conventional drug delivery formulation techniques, as taught by Lin, and further containing PLA, PCL, or other copolymers and blends thereof in particle form, which is demonstrated as a conventional drug delivery formulation, as disclosed by Manoukian, because that would further impose further control of the sustained release characteristics of the drug-loaded MOF, as taught by Lin, Manoukian, and Gao.
Furthermore, the primary reference Liu teaches that a primary feature of MOFs is to control release of a caged therapeutic agent (pg 3123, paragraphs 1 and 2) for enhanced drug delivery efficiency similarly to other nanocarriers (pg 3123, paragraph 4), and Gao provides a specific demonstration of a drug-loaded ZIF-8 MOF that is encapsulated into polymer layers to generate an advanced drug delivery system with sustained drug release behavior (abstract), demonstrating a combined embodiment of the concept of the instant claims.
Claims 1-4, 7-8, 12-13, 15-19, 22, 26, and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Theranostics 2019, published 5/18/2019), Lin (US20160346204A1), Manoukian (J. Appl. Polym. Sci., 2018), and Gao (Scientific Reports, 2016), as evidenced by Chemistry Views (2013), as applied to claims 1-4, 8, 16-19, 22, 26, and 41, and in further view of Zhang (Adv. Funct. Mater., 2016) and Li (ACS Appl. Mater. Interfaces, 2018; common author, but published on 3/19/2018, qualifying it as prior art under 102(a)(1)).
As discussed above, the references teach MOFs for general use in drug delivery for medicine, including incorporation of a variety of therapeutic agents (such as small molecules, proteins, etc.), and adapting general drug formulation techniques for sustained release. However, they do not teach therapeutic agents such as a vaccine that comprises no additional immunostimulatory adjuvants (instant claim 7 and 42), virus (instant claims 12-13), or attenuate/inactivated virus (instant claim 15).
Zhang teaches OVA@ZIF-8 MOFs as a vaccination strategy, where the OVA protein is encapsulated in ZIF-8 MOF (abstract), promoting OVA-specific antibodies in an immune reaction (Scheme 1). Zhang also teaches the benefits of using a subunit vaccine based on protein antigens as an alternative to traditional live-attenuated or killed pathogen vaccines (introduction). Furthermore, Zhang tests OVA@ZIF-8 (25 ug/mL) in immunization experiments (pg 6458, Figure 3A), where OVA@ZIF-8 (i.e., no CpG present) has immunomodulatory activity through TNF-alpha secretion (pg 6457, paragraph 2) compared to the ‘control’ (see data reprint in ‘response to amendment’ section below).
Li teaches MOFs to deliver tobacco mosaic virus (abstract). Although Li does not specify the TMV as live attenuated or inactivated, it would be obvious to make this modification to a virus, as taught by Zhang above, in order to develop a vaccination strategy based on non-virulent virus.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Liu to apply either an antigenic agent or an inactivated/attenuated virus incorporated in the MOF for immunotherapeutic application, because Zhang teaches MOFs (such as OVA@ZIF-8) as a tool to deliver antigenic material for vaccination, and Li teaches virus incorporation into a MOF.
Furthermore, the combination of these references would have led to the obvious vaccination strategy incorporating live attenuated/inactivated virus, where Zhang’s OVA antigenic agent is replaced by a live attenuated/inactivated virus (representing the antigenic material). The reason for the substitution would be functional equivalence of an antigenic agent and a live attenuated/inactivated virus in terms of their function for a vaccine, as taught by Zhang: The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Also, remember that Li has already demonstrated incorporation of a virus into a MOF (abstract), and Liu teaches therapeutic agents of different sizes can be incorporated by tuning pore size (pg 3122, paragraph 1), suggesting reasonable possibility of success in this endeavor.
Response to Arguments
Applicants arguments, see pg 4-8, filed 10/15/2025, with respect to the 103 rejection of claims 1-4, 7-8, 10, 12-13, 15-19, 22, and 26 under rejection have been fully considered, but they are not persuasive. The 103 rejection has been modified with respect to amendments made to the claim set and new added claims. The thrust of the rejection remains the same as before, relying on the same references.
On page 4, Applicant discusses amendments to claims 8 and 10, which are found acceptable to resolve the 112b issue. Note the newly introduced 112b issue of antecedent basis in the rejection above.
On page 4-5, Applicant argues that the Action fails to establish a prima facie case of obviousness and proceeds to cite case law with the only argument, being a general suggestion that a conclusory assertion with no explanation was made. The Examiner has provided multiple instances of rationale for combination, and directs the Applicant to the 103 rejection above.
On page 6-7, Applicant argues that the claims have been amended such that they demonstrate non-obviousness in view of the cited references. Applicant argues none of the cited references teaches polymer particles around one or more encapsulated therapeutic agents (by specifically suggesting Lin and Gao as deficient in this regard). In direct response to this argument, the Examiner directs Applicant to Manoukian (applied in the 103 rejection above with proper rationale to combine with the other references for an obviousness rejection) who teaches controlled release of drug formulations by using polycaprolactone (PCL), polylactic acid (PLA), copolymers such as PLGA, or combinations thereof (reads on polymers of instant claims 1, 17-19, and 22), where polymer selection, size, and shapes of injectable hydrogels (reads on instant claim 26) depend on target application (pg 2-3, introduction). Manoukian teaches several microsphere formulations have been explored for delivering drugs and release profiles were altered by changing particle size and drug content in the formulation (pg 3, paragraph 1). Rationale is provided in the 103 rejection for combining Manoukian with the Liu reference, making the instantly claimed feature as obvious.
On page 7-9, Applicant submits an Affidavit, as a demonstration of non-obviousness. The response to the Affidavit is discussed in the ‘response to amendment’ section below, and is not found persuasive. Note that in contrast to the arguments presented by Applicant, Zhang in fact demonstrates an immunogenic effect of OVA@ZIF-8 through TNF-alpha section (pg 6458, Figure 3A). Applicant has not provided enough information to distinguish this data from Zhang demonstrating an immunological effect of OVA@ZIF-8 from the instant invention as argued, and thus, the arguments are not persuasive (see below ‘response to amendment’ section for more analysis).
Response to Amendment
The affidavit under 37 CFR 1.132 filed 10/15/2025 is insufficient to overcome the rejection of claims 1-4, 7-8, 10, 12-13, 15-19, 22, and 26 based upon the 103 rejection as set forth in the last Office action because:
First, the scope of the affidavit is narrowed to MOF-containing vaccine compositions. The full claim scope is far broader than the subject matter of the affidavit (i.e., one cannot demonstrate non-obviousness for all therapeutic agents of claim 1, by providing data on only vaccine encapsulated MOF formulations). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). Thus, the current claim scope of a number of claims appears too broad with regard to the proposed unexpected effects at issue.
Second, the affidavit claims that the MOF material itself contributes to immune activation. However, Zhang (the Art Applicant specifically uses to provide contrast to the instant invention) uses the exact same ZIF-8 platform. In this instance, it appears that Applicant has only discovered an unappreciated property of the well-known ZIF-8 platform, which does not entitle one to patentability of a composition: “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property, which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In particular, Zhang teaches OVA@ZIF-8 and OVA@ZIF-8-CpG MOFs (pg 6455, Scheme 1 and paragraph 3), which is similar to the subject matter of Figure A1, Exhibit B of Applicant’s Affidavit (pg 5). Furthermore, Zhang tests OVA@ZIF-8 in immunization experiments (pg 6458, Figure 3A), where OVA@ZIF-8 (i.e., no CpG present) has immunomodulatory activity through TNF-alpha secretion compared to the ‘control’, as reprinted below (next to the data from the Affidavit), which Zhang attributes to an immunological effect. Thus, Applicant is claiming a novel immunological effect for OVA@ZIF-8, in which Zhang demonstrates a similar immunological effect, using the biomarker TNF-alpha (versus Applicant claiming IFN-gamma activity) (see Figures below):
Zhang:
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;
Instant Affidavit:
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It is unclear from the both the arguments and the claim scope what the actual limiting differences there are between the instant claim scope and the Zhang disclosure (in combination with the other Prior Art on record). The Applicant appears to be arguing specific technical limitations that are not specifically represented in the claim scope: Constant v. Advanced Micro-Devices, Inc., 848 F.2d 1560, 1571-72, 7 USPQ2d 1057, 1064-1065 (Fed. Cir.), cert. denied, 488 U.S. 892 (1988) (Various limitations on which appellant relied were not stated in the claims; the specification did not provide evidence indicating these limitations must be read into the claims to give meaning to the disputed terms.); In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993) (although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims). Note that the claim scope does not even narrow down to the species of OVA@ZIF-8, as discussed by Applicant, but claims a much broader scope.
Also, on the face of it, it also appears that Zhang’s OVA-ZIF-8 (which demonstrates an immunogenic TNF-alpha activity) is being compared with the instant u-OVA@ZIF-8 (which is not specifically limited in the instant claim set; however, the ‘mu’ modifying u-OVA only seems indicate mouse vs. ‘n’ for native, as in Figure A3, as the only noticeable difference in terminology, in which it is obvious to use mouse or native OVA). The Examiner has not been provided with enough information to discern the difference between the OVA@ZIF-8 species as taught by Zhang and by the Affidavit for the purpose of determining patentability. Thus, Applicant’s instant u-OVA@ZIF-8 and its immunological effect does not teach anything more than what the skilled artisan would expect to see from encapsulating a vaccine antigen in a MOF, as demonstrated by Zhang.
Finally, because the OVA@ZIF-8 is not Zhang’s preferred embodiment, that does not constitute a teaching away: In order to teach away from a proposed modification, the art must “criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). The art does not criticize, discredit, or otherwise discourage the modification proposed by the Examiner. Furthermore, an obvious composition suggested as inferior does not afford patentability: In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." Just because the OVA@ZIF-8 taught by Zhang does not have the highest activity of the materials tested in the disclosure does not afford patentability to another Applicant.
Correspondence
Applicant's amendment necessitated the new ground 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 extension fee 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 date of this final action.
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/R.P./Examiner, Art Unit 1614 11/13/2025
/SEAN M BASQUILL/Primary Examiner, Art Unit 1614