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 08/14/2026 has been entered. Applicant’s amendments are in response to the Non-Final Office Action mailed 05/15/2026. Applicant’s claims have been amended in the following manner: independent claim 1 has been modified by broadening of the definition of “biologic agent” by eliminating the Markush list, and narrowing to “a plurality of the MOF-encapsulated biologic agents dispersed within the matrix”, with additional minor changes to the sustained release limitation. Claim 41 now relies on claim 1 due to cancellation of claim 8.
Furthermore, newly-added claim 43 introduces new limitations of “wherein the embedded microparticle has a diameter of about 10 um to about 100 µm, and the MOF-encapsulated biologic agent has a diameter of about 0.3 µm to about 1 µm.” The new amendment of claim 43 is reasonably supported by the Specification: Figure 15A shows about 20 um diameter ZIF-8@PLGA microparticles (reasonably representing embedded microparticle) ; Figure 14A shows about 1 um diameter Cy5@ZIF-8 (reasonably representing MOF-encapsulated biologic agent).
The 103 rejection has been modified toward a new ground of rejection (incorporating Lewis to explicitly teach the “dispersed” limitation). Furthermore, the newly added claim 43 is rejected on a new ground of rejection (incorporating Lewis and Nordin).
The Examiner further acknowledges the following:
Claims 1-2, 7, 12, 15-19, 22, 26-27, 30, 34, 36, and 41-43 are pending.
Claims 27, 30, 34, and 36 are withdrawn from consideration as directed to non-elected inventions.
Claims 1-2, 7, 12, 15-19, 22, 26, and 41-43 are presented for examination and rejected as set forth below.
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.
Claims 1-2, 7, 12, 15-19, 22, 26, and 41-43 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.
Claims 1 and 43 recites “about” (i.e., introduced by amendment), in which “about” is a relative term, that is indefinite, and does not provide a definite interpretations of the metes and bounds of the invention. Applicant defines “about” in the Specification: “Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects or patients.” This definition does not provide a definite instruction in how to interpret “about” in claims 1 and 43. Therefore the Examiner will consider the values of claims 1 and 43, as if there was no “about”. For example, for claim 1, the Examiner interprets the time period as “at least 6 days” (i.e., 6 days or longer).
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 1-2, 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), and in further view of Lewis (US20020155158A1), Lin (US20160346204A1), Manoukian (J. Appl. Polym. Sci., 2018), and Gao (Scientific Reports, 2016).
Applicant’s independent claim 1 recites an embedded microparticle composition comprising, a biologic agent encapsulated in a metal-organic framework (MOF), and the MOF-encapsulated biologic further embedded in a matrix of one or more biodegradable polymers to form an embedded microparticle, with “a plurality of the MOF-encapsulated biologic agents dispersed within the matrix”, wherein the composition providing sustained release of the biologic agent over at least 6 days. Applicant further specifies particle/agent diameter in instant claim 43.
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 1-2 and 41: Liu teaches the polypeptide insulin encapsulated (reads on “MOF-encapsulated biologic 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 (reads on the species of claim 2) (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). Liu also teaches controlled release (pg 3124, paragraph 2) and improved biostability, as advantages of MOF-encapsulated agents (abstract).
Regarding claim 16: Liu teaches immunotherapy (pg 3128, paragraph 2).
In summary, Liu teaches a composition comprising “MOF-encapsulated biologic agent” for the purpose of drug delivery, especially for controlled release and biostability. However, Liu does not teach the pharmaceutically acceptable polymers of the formulation to form an embedded microparticle with “a plurality of the MOF-encapsulated biologic agents dispersed within the matrix” (instant claims 1, 17-19 and 22), administration by injection (instant claim 26).
Lewis teaches a general strategy for controlled release of bioactive molecules by encapsulating them within a biodegradable polymer such as PLAs, PGAs, (claim 3). Thus, Lewis teaches the biological active can be in solution or dispersed, followed by spray-drying, leading to the active agents being dispersed within the composition (reads on “a plurality of the MOF-encapsulated biologic agents dispersed within the matrix” of instant claim 1) [0028-0030]. Furthermore, the resulting particles are between 25- 200 μm (reads on the “embedded microparticle has a diameter of about 10 µm to about 100 µm” of instant claim 43, by overlapping the instant range) ([0050, 0060], Table 2). With regard to the numerical range, a prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art (see 2144.05(I)). See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”). Lewis teaches microspheres in a size range of between 25- 200 μm is suitable to achieve biological agent release over days [0008] up to several months [0002], whereby the specific polymeric ingredient can release the agent over several weeks or a period of less than 5 years [0020-0026].
Lin teaches drug-loaded MOF formulations, incorporating chemotherapeutics or nucleic acids (abstract), where the drug-loaded 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) in the form of a nanoscale particle (Lin – claim 1).
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). Manoukian teaches drug release of up to 56 days (reads on the 6 days of instant claim 1, because the time period of 0-56 days encompasses 6 days) (pg 7). While Manoukian does not explicitly teach a “dispersed” active in the polymeric microparticle, Manoukian implies this structure by using the Higuchi model (Equation 2) (i.e., which “describes the release of dispersed drug from a homogeneous matrix using the pseudo steady-state approximation”), for drug release kinetics (pg 8, ‘drug release kinetics’).
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). Gao also demonstrates drug release profiles over 40 hours (pg 7, Figure 9).
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 MOF-encapsulated biologic into a dispersed formulation, as taught by Lewis, because Lewis teaches dispersed formulations [0028-0030], as one of many formulation types that provide controlled release of biologic molecules, that achieves biological agent release over days [0008] up to several months [0002], whereby the specific polymeric ingredient can release the agent over several weeks or a period of less than 5 years [0020-0026].
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 MOF-encapsulated biologics with an injectable formulation (reads on instant claim 26), using conventional drug delivery formulation techniques, as taught by Lin, and further containing PLA, PCL, or other copolymers and blends thereof in particle form (reading on instant claims 1, 17-19, and 22), which is demonstrated as a conventional drug delivery formulation, as disclosed by Manoukian and Lewis, 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, bearing the advantages of combining such features, such as biostability and sustained release, as already discussed.
Claims 1-2, 7, 12, 15-19, 22, 26, and 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Theranostics 2019, published 5/18/2019), Lewis (US20020155158A1), Lin (US20160346204A1), Manoukian (J. Appl. Polym. Sci., 2018), and Gao (Scientific Reports, 2016), as applied to claims 1-2, 16-19, 22, 26 and 41, and in further view of Zhang (Adv. Funct. Mater., 2016), Li (ACS Appl. Mater. Interfaces, 2018; common author, but published on 3/19/2018, qualifying it as prior art under 102(a)(1)), and Nordin (2014), as evidenced by American Society for Microbiology (2018).
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, nucleic acids, proteins, etc.), and adapting general drug formulation techniques for biostability and sustained release (i.e., up to weeks sustained delivery). Additionally, Lewis teaches microspheres in a size range of between 25- 200 μm (reads on “embedded microparticle” 10-100 um diameter of instant claim 43, because it overlaps the instant range) is suitable for controlled release of several days [0008] up to several months [0002]. However, they do not teach therapeutic agents such as a vaccine that may also comprise no additional immunostimulatory adjuvants (instant claim 7 and 42), a microbial antigen (instant claims 12), attenuated/inactivated vaccine (instant claim 15), or the “MOF-encapsulated biologic agent” diameter of 0.3-1 um (instant claim 43; other diameter requirement).
Zhang teaches OVA@ZIF-8 MOFs as a vaccination strategy, where the OVA protein antigen (reads on instant claim 7) (pg 6455, paragraph 2) 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 (reads on instant claim 15) (introduction). Furthermore, Zhang tests OVA@ZIF-8 (25 ug/mL) in immunization experiments (pg 6458, Figure 3A), where OVA@ZIF-8 (i.e., there is no immunogenic CpG (that is generally present in bacterial/viral DNA, as stated on pg 6455, paragraph 2), and thus, does not include an additional immunostimulatory adjuvant, as in instant claim 42) has immunomodulatory activity through TNF-alpha secretion (pg 6457, paragraph 2) compared to the ‘control’ (see data reprint in ‘response to amendment’ section below), whereby TNF-alpha is produced during a Th1 type immune response, where IFN-g response would also be expected (pg 6457, paragraph 2).
Li teaches MOFs to deliver tobacco mosaic virus (reads on instant claim 12) (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. Furthermore, as evidenced by American Society for Microbiology, viruses are considered microbial (reads on claim 12) (pg 2).
Nordin teaches synthetic methods for MOFs such as ZIF-8 (abstract), and also commercial sources of MOFs, that have variable sizes based on production method (abstract, Table 1). For example, Nordin teaches ZIF-8 particle sizes of 493 nm (or 0.493 um) (i.e., incorporation of an active molecule into the ZIF-8 would not be expected to further increase the particle size, because the active is retained inside of the ZIF-8, and thereby does not affect the final diameter of the MOF-encapsulated biologic agent complex; see Liu - Figure 2, pg 3125 below) in Z500 (Table 1) (reads on MOF-encapsulated biologic agent has a diameter of about 0.3 µm to about 1 µm of instant claim 43).
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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.
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 the combined Prior Art by selecting a MOF with a particle size of 493 nm (such as Z500), as taught by Nordin. One of ordinary skill in the art would make size modification of the MOF-encapsulated biologic agent, because Nordin teaches MOFs can be made in different nanoparticle sizes based on production method, and Liu teaches MOF nanoparticles with tunable pore sizes and controllable structures, who also teaches tunable overall size of MOF structures (see Liu - fig 4, pg 3127 below; pg 3130).
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With regard to the other numerical range of instant claim 43 (i.e., the instant range for the embedded microparticle) Lewis teaches microspheres in a size range of between 25- 200 μm (i.e., overlapping the instant range of 10-100 um) is suitable for controlled release of several days [0008], where Liu is interested in the controlled release of active agents (abstract, pg 3123).
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 1-4, filed 08/14/2026, with respect to the 103 rejection of claims 1-2, 7, 12, 15-19, 22, 26, and 41-42 have been fully considered and are persuasive. However, the 103 rejection has been modified toward a new ground of rejection (incorporating Lewis to explicitly teach the “dispersed” feature). Furthermore, the newly added claims are rejected on a new ground of rejection (incorporating Lewis and Nordin). Furthermore, additional evidentiary references are provided below (see Gibson and Morita), to provide objective evidence, that serves to rebut Applicant’s arguments.
On page 1, Applicant discusses changes made to the “sustained-release limitation”. However, there are issues with the limitation of “at least about 6 days” (see 112(b) above, that needs to be resolved; see also claim 36).
On page 1-2 (‘first’), Applicant argues that none of the references alone or in combination teaches or suggests this specific embedded microparticle structure. In this case, there is an aspect of this argument that suggests a piecemeal analysis (i.e., “alone”), which is per se unpersuasive. It is the combined teachings that define the art, where the combination of the Art provides a prima facie case of obviousness. Additionally, Applicant is suggesting that the references cannot be combined for bodily incorporation and/or do not represent all elements of the instant claims: The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Furthermore, “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. At 420, 82 USPQ2d 1397. On a very basic level, the Examiner relies on each reference as a building block that would be rationally combined by a PHOSITA to arrive at the subject matter of the instant claims (see 103 rejection). Thus, 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). Gao teaches actives encapsulated in MOFs within polymeric layers, enabling the combination of an MOF encapsulated active, that is further embedded by a polymeric ingredient. Manoukian and Lewis teach polymeric microspheres that encapsulate active agents, including methods of making that disperse the active. Therefore, a MOF-encapsulated biologic agent dispersed within a polymeric matrix, for the purpose of controlled release is obvious based on the combined Prior Art. The combination of these general elements renders the broader inventive concept of the instant composition, as obvious to a PHOSITA.
Furthermore, Applicant has provided no objective evidence that the modification proposed by the Examiner in the 103 rejection is not enabled by the combined Prior Art. By contrast, the Examiner provides evidence, that it is well known in the Art, whereby Gibson (US6291013) teaches encapsulation of any substance and/or active agent (col. 6, ‘E. Active Agent’) into a microparticle, as well-known to the Art (abstract), and MOF-encapsulated biologics are known substances and/or actives.
As for the assertion that the rejection is based on hindsight, as noted in MPEP 2145, “[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). The Examiner has pointed to nothing other than what the art available at the time the instant application was filed to teach or suggest each and every limitation of the invention claimed, and relied on nothing other than the art to rationalize their combination in the manner put forth.
Concurrently, Applicant attacks each reference piecemeal (i.e., “no single reference supplies the claimed structure”). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Each reference is not required to teach all elements.
Finally, Applicant states Lin and Gao point away from a matrix structure. 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). In this case, the embodiment of a polymeric shell of Lin and/or Gao provides no information regarding polymeric dispersions. The further criticism that no single reference supplies the complete claimed structure is a piecemeal argument that is per se unpersuasive. Lastly, an obviousness analysis incorporates the combined teachings of the Prior Art, and this considers the newly incorporated reference Lewis. Lewis teaches the biological active can be in solution or dispersed, followed by spray-drying, leading to dispersed compositional structure of the final product (reads on “a plurality of the MOF-encapsulated biologic agents dispersed within the matrix” of instant claim 1) [0028-0030], whereby Lewis further teaches microparticle and/or nanoparticle forms of compositions comprising biological actives and biodegradable polymers, generally (abstract). Thus, the concept of actives dispersed within a “matrix architecture” is made obvious by Lewis, along with other references that discuss compositions comprising actives and/or MOFs further mixed within polymeric ingredients, for the purpose of controlled release.
On page 2-3 (‘second’), Applicant argues no reasonable expectation of success while retaining biologic function: With regard to reasonable expectation of success: “Applicants are reminded that obviousness does not require absolute predictability. See In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976) (indicating that evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness).” Furthermore, Applicant has not provided evidence that unpredictability of the art to challenge the obviousness of the modification. Additionally, the rationale of the 103 rejection does not rely on the process methods of Manoukian and Makadia, but relies on the structures that they describe. Finally, the combined Prior Art demonstrates compatibility of “MOF encapsulation” and “microparticle embedding” with biologics (see 103 rejection), and thus, a PHOSITA would have no reason to question the combination of all features of the instant claim scope.
Furthermore, Applicant argues that the release duration is unexpected. However, as a counterpoint, the release period found in instant claim 1 (i.e., “over a period of at least 6 days”) is rendered obvious by the combined Prior Art (especially, for actives encapsulated into polymeric microparticles). Thus, Lewis teaches biological agent release over days [0008] up to several months [0002], whereby the specific polymeric ingredient can release the agent over several weeks or a period of less than 5 years [0020-0026]. Manoukian teaches drug release of up to 56 days (reads on the 6 days of instant claim 1, because the time period of 0-56 days encompasses 6 days) (pg 7).
Applicant further argues that Manoukian and Makadia use organic solvents that would denature all biological agents (without providing objective evidence that all claimed biological agents, such as peptide, nucleotide, virus, etc., would denature under organic solvent conditions, in support of this argument). In support of this argument, Applicant states that the s/o/w process (for smURFP, in Example 4) used in the instant example, allows for biologics to remain intact. On pg 56, Applicant’s s/o/w process contains the following organic materials: PEG-6000 and dichloromethane. Thus, it is unclear what distinction Applicant is attempting to make.
As evidentiary rebuttal, Gao only uses deionized water in “Preparation of ZIF-8/5-FU@FA-CHI-5-FAM” (pg 8). Furthermore, Lewis (introduced to address new claim amendments) teaches formulations and methods of making polymer encapsulated proteins, peptide, and oligonucleotides (abstract). Thus, these biological agents retain their structure and bioactivity during the polymeric encapsulation process (abstract, [0002], Lewis – claim 6). Furthermore, Morita (J. of Controlled Release, 2000) teaches a S/O/W emulsion method using PEG is known method to encapsulate proteins, without denaturing the protein (abstract).
Furthermore, the limitations of a specific process are not claimed in the instant claim scope (i.e., there is no exclusion of organic solvents within a product-by-process type limitation). Limitations are being argued that are not claimed: 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). Furthermore, if Applicant argues unexpected results that are associated with the process, then the claims must be commensurate in scope with the unexpected results (i.e., the limitations of the claim would consistently lead to the unexpected result, without omitting essential limitations that provide that unexpected result). At the moment, an unexpected result is not provided, that differentiates the claims from the teachings of the combined Prior Art.
In rebuttal to criticisms of Gao and Zhang (see paragraph 1, pg 3 of Remarks), the Examiner points to Lewis and Manoukian, where it is the combined teachings of the Art that provide the knowledge available to a PHOSITA at the time of filing. Thus, Lewis teaches biological agent release over days [0008] up to several months [0002], whereby the specific polymeric ingredient can release the agent over several weeks or a period of less than 5 years [0020-0026]. Manoukian teaches drug release of up to 56 days (reads on the 6 days of instant claim 1, because the time period of 0-56 days encompasses 6 days) (pg 7). Manoukian attributes the sustained release period to the polymeric encapsulation, which does not depend on the nature of the small molecule housed inside of the MOF (which is supported by the sustained release demonstrated by Lewis for biologic agents).
In summary, regarding the purported unexpected results overall, Lewis teaches biological agent release over days [0008] up to several months [0002], whereby the specific polymeric ingredient can release the agent over several weeks or a period of less than 5 years [0020-0026]. Manoukian teaches drug release of up to 56 days (reads on 6 days of instant claim 1, because the time period of 0-56 days encompasses 6 days) (pg 7). Thus, the extended release of “at least 6 days” provided by Applicant is an expected result, because of the additive effect of controlled release of the biologic encapsulated by a MOF, plus the controlled release of actives encapsulated by polymeric ingredients, as taught by the combined Prior Art. Note, that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Consequently, we must determine whether the results obtained in the closest prior art and those set forth by Applicants are sufficiently different in kind, and not merely in degree, so as to be unexpected by a person of ordinary skill in the art at the time of invention. See Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (Unexpected results that are probative of nonobviousness are those that are "different in kind and not merely in degree from the results of the prior art") (citation omitted). In this case, the Prior Art demonstrating sustained release of active from days to months simply by polymeric encapsulation alone, already demonstrates the instant “at least 6 days” sustained release timeframe, as expected.
Thus, the unexpected result argument is not persuasive. To counteract an obviousness rejection: “[A]ppellants have the burden of explaining the data…they proffer as evidence of non-obviousness.” Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992). The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). If there is something particular about the manufacturing process and/or composition that contains an unexpected result, it is the burden of the Applicant to successfully argue this unexpected result.
On page 3 (‘final’), Applicant argues that there is no motivation to combine the references, stating that “further control of sustained release” is a goal of Applicant’s and not the Art. Note that, in an obviousness analysis, the combined Art is not required to have the exact motivation of Applicant’s: In an obviousness analysis, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
Furthermore, note that control vs. “further control” is semantic argument that does not find particular weight as a substantive argument. Additionally, the Examiner points out that Makadia, Manoukian, and Lewis all independently teach general polymeric “embedded microparticles” of active agents, as a common way of providing controlled release for active molecules, whereby Gibson (US6291013) teaches encapsulation of any substance and/or active agent (col. 6, ‘E. Active Agent’) into a microparticle, using generic methods of preparation involving solutions/dispersions (col 1, ‘background of invention’), to provide controlled release (col 8, lines 3-7), as well-known to the Art (abstract). Furthermore, Liu teaches controlled release (pg 3124, paragraph 2) and improved biostability, as advantages of MOF-encapsulated agents (abstract), and Gao provides an example 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), thus demonstrating compatibility of MOFs and polymeric encapsulation. Thus, in this case, the Art provides the same (as Applicant) motivation for combining MOF encapsulated actives with polymeric embedding into microparticles, as a means to provide additive controlled release and/or orthogonal controlled release of an active agent.
Finally, Applicant further criticizes the Art for individual references not containing all elements of the claim scope, or criticism of specific embodiments of particular references, when the Examiner reiterates the teachings and/or specific embodiments of a single reference are not representative of the Art, but instead it is the combined teachings that provide the foundation for an obviousness analysis. Thus, Applicants specific arguments against the obviousness of the instant claims are not persuasive.
On page 3, Applicant discusses support for new claim 43, which is addressed by a new ground of rejection (see 103 above, for full details).
On page 3-4, Applicant requests an interview. Applicant is welcome to schedule an interview upon receipt of this Office Action, if desired (i.e., my SPE would attend the meeting). Currently, the Examiner has sufficient information in the remarks, to advance prosecution beyond the current amendments and arguments. Thus, the focus remains on the current amendments and remarks document. The Examiner believes that the Applicant will find the additional information in this Office Action will lead to a better understanding of the prosecution status.
On page 4, Applicant concludes. The claims remain under rejection of obviousness.
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).
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/R.P./Examiner, Art Unit 1614 9/3/2026
/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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