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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Aug. 28, 2025 has been entered. All arguments, amendments to the specification, and the IDSs submitted on Nov. 11, 2025, Jan. 17, 2025, Feb. 21, 2025, May 21, 2025, and Aug. 28, 2025 have been fully considered.
Information Disclosure Statement
It is noted that Applicants have submitted and continue to submit IDS's with their application. These bring the number of cited Prior Art Non-Patent Literature to about 482 items, Foreign Art references to about 140 items and US Patent references to about 60, the total is about 682 references. Many of these references are general in nature to the invention at hand and appear to have no discernable relevance at all. Applicants are advised that the Office has very limited time in which to consider IDS submissions.
Applicants are requested to point out which references are most pertinent to the patentability of the instant claims and to the point of novelty. This request is not a formal request for information under 37 CFR 1.105, but an informal request to help expedite prosecution, focus Examiner's attention on the substantive issues in this case, and ensure the validity and therefore the value of any patent that might issue from the instant application. Applicants' cooperation with this request would be most appreciated.
More importantly, Applicants are advised that the instant application was filed on Jan. 15, 2021, which is after Sep. 16, 2012. This application is covered by most of the provisions of the AIA . It is not a first-inventor-to-file application, but it is covered by the AIA rules for Inventors’ Declarations and Oaths. Under the AIA rules, Applicants no longer have the duty of disclosure. They are no longer required to disclose material that they consider to be relevant to patentability or other prior art. See 35 USC § 115, section 4 of the AIA (125 Stat. 284, Public Law 112-29, http://www.uspto.gov/aia_implementation/20110916-pub-l112-29.pdf) and form PTO/AIA /01.
Status of the Claims
Claims 1-7, 10, 13, 15, 16, 18-21, 24 and 25 are currently pending.
Claims 1 and 10 are amended.
Claims 20, 21, 24 and 25 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 8, 9, 11, 12, 14, 17, 22, 23, 26 and 27 are cancelled.
Claims 1-7, 10, 13, 15, 16, 18 and 19 have been considered on the merits.
Drawing Objections
The drawing objections are withdrawn due to amendment.
Claim Rejections - 35 USC § 112
New claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ) have been added to address the claim amendments.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7, 10, 13, 15, 16, 18 and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventors, at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a limitation of “wherein the composition comprises a burst-suppressed release profile in which <20% of the insulin is released in the first 24 h while ≥25% of the vitamin D is released in the same period”. The specification appears to describe where <20% insulin (INS) is released in the first 24 h when combined with PLGA microparticles (MP) and fibrin gel (Fig. 1G and 5G). However, there appears to be no description whether this release profile for insulin is a burst-suppressed release profile and there is no release profile description for vitamin D in a fibrin gel.
Claim 10 recites a limitation of “wherein the microparticles are surface modified with polyethylenimine (PEI)”. The specification appears to describe the scaffold containing PEI (0005 and 0008, 0055) and the first and second delivery vehicles containing PEI (0006, 0056-0057), but there appears to be no description of the microparticles being surfaced modified with PEI or any surface modification to the microparticles.
This is a new matter rejection.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
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.
Claims 1-6, 13, 15, 16, 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Khorsand et al. (Journal of Controlled Release, available online Jan. 7, 2017) (ref. of record) in view of Son et al. (Journal of Biomaterials Applications, 2015) (ref. of record), Zhang et al. (Bioactive Materials, Mar. 2018) (ref. of record), Fonseca-Santos et al. (Materials Science and Engineering, Aug. 2017) (ref. of record) and Han et al. (Science China Life Sciences, 2012) and as evidenced by Khang et al. (NanoScience in Biomedicine, 2009).
With respect to claim 1, Khorsand teaches a composition containing a scaffold loaded with nucleic acids encoding BMP-2 and FGF-2 for bone regeneration (abstract and pg. 54 Col. 1 para. 2). With respect to claim 2, Khorsand teaches the nucleic acids are plasmid DNAs (abstract). With respect to claims 3 and 4, Khorsand teaches the scaffold contains collagen (abstract). With respect to claims 5, 6, 13 and 15, Khorsand teaches the plasmid DNAs encoding BMP-2 and FGF-2 are complexed with polyethylenimine (PEI) which is incorporated into the scaffold (abstract). One would understand the complex would act as a delivery vehicle as recited in claims 13 and 15.
Khorsand does not teach the composition containing a fibrin gel core loaded with insulin and at least one form of bioavailable form of vitamin D and where the scaffold surrounds the gel core as recited in claim 1. Additionally, Khorsand does not teach the insulin is complexed with a first delivery vehicle containing poly(lactic-co-glycolic) acid (PLGA) microparticles as recited in claim 1.
However, Son teaches platelet-rich plasma with hyaluronic acid and gelatin (a gel) loaded in a biphasic calcium phosphate scaffold for bone defect healing (a scaffold encapsulating or surrounding a gel core for treating bone injury) (abstract).
Zhang reports scaffolds have been loaded with biofactors including BMP, IGF, TGF-beta, VEGF, PDGF, FGF, insulin and nucleic acids for bone regeneration (pg. 135 para. 2). Zhang teaches synthetic polymers that have been used for bone regeneration include PLA and PL (pg. 135 para. 2) and teaches collagen has been used a scaffold material for bone regeneration (abstract).
Fonseca-Santos teaches hydrogels containing vitamin D3 for the controlled release of vitamin D3 (Table 1). Fonseca-Santos teaches the hydrogel composition containing CMCS (carboxymethyl chitosan) (Table 1) and teaches CMCS based scaffolds have been used in compositions for bone regeneration (pg. 1350 Col. 2 para. 6) and that it enhances bone regeneration (pg. 1351 Col. 1 para. 1). Fonseca-Santos teaches hydrogels for the delivery of agents for bone and tissue regeneration and teaches a gel containing fibrin for tissue regeneration (pg. 1350 Col. 2 para. 5). Fonseca-Santos further teaches that fibrin promoted cell adhesion to the scaffold (pg. 1350 Col. 2 para. 5).
Han teaches that insulin delivery using a composition of a fibrin gel loaded with insulin/poly(lactic-co-glycolic acid) microspheres improves the retention of titanium implants in type 1 diabetic rats for bone repair (abstract and pg. 2299 para. 1). Han further reports that in a previous study that insulin encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres to provided sustained insulin delivery at the implant-bone interface in type 2 diabetic rats and that the insulin released from the PLGA microspheres over 14 days improved the poor-quality osseointegration” (pg. 2300 Col. 1 para. 1). Han teaches the benefits of using fibrin gel include that it acts as a scaffold for cell attachment and growth since it contains many growth factors and by incorporating microspheres into the fibrin gel the burst release can be decreased and a more sustained release time can be achieved then with microspheres alone (pg. 2300 Col. 1 para. 1).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the bone regeneration composition of Khorsand to include a fibrin gel core loaded within or surrounded by a scaffold and containing the additional factors of insulin and vitamin D for the benefit of including additional components and factors known to benefit bone regeneration as taught by Son, Zhang, Fonseca-Santos and Han. One skill in the art would have been motivated to complex the insulin in the fibrin gel with PLGA microspheres for the benefit of the sustained delivery of insulin from the fibrin gel which is also beneficial as a scaffold and source of growth factors as taught by Han and Fonseca-Santos. Furthermore, one of ordinary skill in the art would have been motivated to modify the composition of Khorsand to include a fibrin gel core encapsulated or surrounded by the scaffold and complexed with vitamin D3 and insulin for the benefit of including additional well-known components that aid in bone regeneration as taught by Zhang, Fonseca-Santos and Han in a form that allows for the controlled release as taught by Fonseca-Santos and Han and where the gel is within the scaffold which has the appropriate mechanical and regeneration properties needed for an implant for bone regeneration as taught by Son and Khorsand (Son, pg. 989 para. 1; Khorsand, pg. 58 last para.). It would have been obvious to one of ordinary skill in the art to modify the composition of Khorsand to include a fibrin gel core loaded within or surrounded scaffold and containing the additional factors of insulin complexed with PLGA microparticles and vitamin D, since scaffolds containing gel cores were known for use in bone regeneration compositions as taught by Son and both insulin and vitamin D were known to be used in hydrogels and/or scaffold of bone regeneration compositions as taught by Zhang, Fonseca-Santos and Han. One of ordinary skill in the art would have had a reasonable expectation of success in modifying the composition of Khorsand to include a fibrin gel core loaded within or surrounded scaffold, since similar compositions for bone regeneration were known to have gels contained within a scaffolds as taught by Son. One of ordinary skill in the art would have had a reasonable expectation of success in modifying the composition of Khorsand and Son to further include insulin and vitamin D in the component gel, to have the insulin complexed with PLGA microparticles, and for the gel to be fibrin, since Fonseca-Santos teaches hydrogels containing vitamin D3 for bone regeneration, Zhang teaches scaffolds containing insulin and nucleic acids encoding for growth factors for bone regeneration and Han teaches fibrin gels containing insulin complexed with PLGA microparticles.
None of Khorsand, Son, Zhang, and Fonseca-Santos teach the composition where the release profile of insulin and vitamin D from the composition and Han reports a burst release of 37% within the first 24 hours of insulin for a composition of fibrin gel with insulin complexed with PGLA microspheres (pg. 2303 Col. 1 last para.). None of Khorsand, Son, Zhang, Fonseca-Santos and Han teach the composition with a burst-suppressed release profile in which <20% of the insulin is released in the first 24 h while ≥25% of the vitamin D is released in the same period. However, one of ordinary skill in the art would recognize that these characteristics of the composition and gel are result effective variables and that the release profile of the bioactive factors of the composition would be matter of routine optimization as evidenced by Khang. Khang reports that by placing bioactive molecules into delivery vehicles containing biomaterials the efficacy of bioactive molecules can be improved by locally controlling the release of the bioactive molecules at the molecular level for the desired release period (pg. 349 last para.). Additionally, Khang teaches by using delivery vehicles the protein structure and biological activity of the biomaterial can be stabilized to a certain extent resulting in prolonging of the release time at the local site (pg. 349 last para.). Khang teaches that “the duration of release from the delivery vehicles can be controlled by the types of biomaterials used, the loading amount of bioactive molecules, the formulation factors and the fabrication process” (Pg. 349-350 bridging para.). In addition, Khang teaches that the “mechanism of biodegradable delivery vehicles was controlled by degradation controlled, whereas that of nondegradable one was regulated by diffusion and/or solvent controlled. Desired release pattern such as constant, pulsatile, and time programmed behaviors along the specific site and the type of stem cell can be achieved by the appropriate combination of these mechanisms.” (pg. 350 para. 1). Accordingly, the release profile of the composition would have been optimized depending on the bioactive factors and desired purpose of the composition.
Although Khorsand does not teach the claimed use of the composition as recited in claims 16 and 19, the composition taught by combined teachings of Khorsand, Son, Zhang and Fonseca-Santos is the same as those claimed by applicant. Thus, the intended use of the compositing is also inherent in the composition of the prior art references. It is noted that the intended use of the claimed composition does not patentably distinguish the composition, per se, since such undisclosed use is inherent in the reference composition. In order to be limiting, the intended use must create a structural difference between the claimed composition and the composition of the prior art. In the instant case, the intended use fails to create a structural difference, thus, the intended use is not limiting.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 7 is rejected under 35 U.S.C. 103(a) as being unpatentable over Khorsand in view of Son, Zhang, Fonseca-Santos and Han and as evidenced by Khang (as applied to claims 1-6, 13, 15, 16, 18 and 19 above), and further in view of An et al. (Experimental Biology and Medicine, published online May 24, 2017) (ref. of record).
The teachings of Khorsand, Son, Zhang, Fonseca-Santos and Han can be found in the previous rejection above.
None of Khorsand, Son, Zhang, Fonseca-Santos and Han teach the composition where the vitamin D is calcitriol or ercalcitriol as recited in claim 7. Fonseca-Santos teaches hydrogels containing vitamin D3, but is silent with respect to the form of vitamin D3.
However, An teaches vitamin D (1,25-Dihydroxyvitamin D3 or calcitriol) when given with TGF-B and IGF-1 protects against degeneration of intervertebral disc in diabetic rats (abstract).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the combined teachings of Khorsand, Son, Zhang, Fonseca-Santos and Han in such a way that the bioavailable form of vitamin D is calcitriol for the purpose being in composition for bone regeneration. Furthermore, it would have been obvious to one skilled in the art to have further modified the composition taught by combined teachings of Khorsand, Son, Zhang, Fonseca-Santos and Han such that the bioavailable form of vitamin D is calcitriol, since similar compositions for bone regeneration were known to contain the calcitriol of vitamin D3 as taught by An. Such a modification merely involves the substitution of one known type of vitamin for another for a composition for bone regeneration.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 10 is rejected under 35 U.S.C. 103(a) as being unpatentable over Khorsand in view of Son, Zhang, Fonseca-Santos and Han and as evidenced by Khang (as applied to claims 1-6, 13, 15, 16, 18 and 19 above), and further in view of Tan et al. (Peptides, 2010).
The teachings of Khorsand, Son, Zhang, Fonseca-Santos and Han can be found in the previous rejection above.
None of Khorsand, Son, Zhang, Fonseca-Santos and Han teach the composition where the microparticles are surface modified with polyethylenimine (PEI) as recited in claim 10.
However, Tan reports that nanoparticles coated with PEI, for the delivery of an bioactive molecule, BMP-2, had decreased burst release of BMP-2 and increased retention of BMP-2 compared to uncoated nanoparticles (pg. 191 Col. 2 para. 1). Tan further reports that the PEI coating is predicted to delay BSA degradation from the nanoparticles composed of BSA and allows for the delayed release of BMP-2 from the BSA matrix (pg. 191 Col. 2 para. 1)
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the combined teachings of Khorsand, Son, Zhang, Fonseca-Santos and Han in such a way that the microparticles are surface modified with PEI for the purpose being able to further delay the release of the insulin and slow the degradation of the microparticles as taught by Tan. Furthermore, it would have been obvious to one skilled in the art to have further modified the microparticles taught by combined teachings of Khorsand, Son, Zhang, Fonseca-Santos and Han such that the microparticles are surface modified with PEI, since similar microparticles carrying bioactive molecules for use in treating a subject were known to be coated with PEI to improve the release of the bioactive molecule as taught by Tan. One of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the microparticles taught by Han, since Han teaches controlling the release of insulin from microparticles and Tan teaches coating microparticles with PEI helps in controlling the release of bioactive molecules.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Aug. 28, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that none of the references teach a gel that contains insulin and a bioavailable form of vitamin D and where the gel is encapsulated by a scaffold carrying plasmid DNA. Applicant argues there to no reason why one of ordinary skill in the art would combine three incompatible payloads (vitamin D, insulin-polymer complexes and DNA) and expect that they could coexist and maintain bioactivity (Remarks pg. 8-10 bridging para.). However this argument was not found to be persuasive, since each of the components are known in the art for bone regeneration. It is maintained that the combined teachings of Khorsand, Son, Zhang, Fonseca-Santos and now, Han, teach the composition of a scaffold loaded with nucleic acid encoding at least two growth factors surrounding a fibrin gel containing insulin complexed with a PLGA microparticle and at least one bioavailable form of vitamin D. Khorsand is being relied upon for the teaching of a scaffold loaded with nucleic acids encoding BMP-2 and FGF-2 for bone regeneration (abstract and pg. 54 Col. 1 para. 2). Son is being relied upon for the teaching for a scaffold encapsulating a gel with growth factors for treating bone injury) (abstract). Zhang is being relied upon for the teaching of scaffolds containing growth factors, insulin and nucleic acids for bone regeneration (pg. 135 para. 2). Fonseca-Santos is being relied upon for the teaching of gels containing vitamin D3 for the controlled release of vitamin D3 for bone regeneration (Table 1, pg. 1350 Col. 2 para. 6 and pg. 1351 Col. 1 para. 1). Han is being relied upon for a fibrin gel loaded with insulin/poly(lactic-co-glycolic acid) microspheres improves the retention of titanium implants in type 1 diabetic rats (abstract). It is maintained that one of ordinary skill in the art would have been motivated to modify the composition of Khorsand to include a gel encapsulated by the scaffold and complexed with vitamin D3 and insulin for the benefit of including additional known components that aid in bone regeneration as taught by Zhang and Fonseca-Santos in a form that allows for the controlled release as taught by Fonseca-Santos and where the gel is within the scaffold which has the appropriate mechanical and regeneration properties needed for an implant for bone regeneration as taught by Son and Khorsand (Son, pg. 989 para. 1; Khorsand, pg. 58 last para.). When the prior art references are taken as a whole, they teach that the skilled artisan knows each component of the composition as currently claimed.
Applicant argues that the claimed fibrin gel simultaneously contains both insulin microparticles (INS-MP) and vitamin D that is surrounded by a scaffold is not contemplated by the prior art (Remarks pg. 9 para. 2). Applicant’s arguments are drawn to references failing to teach this new limitation. However, this new limitation is addressed in the new rejection.
Applicant argues that none of the references teach a scaffold surrounding a fibrin gel core with insulin in a vehicle that is PLGA microparticles with a burst-suppressed release profile or the claimed release kinetics where <20% of the insulin is released in the first 24 h while ≥25% of the vitamin D is released in the same period (Remarks pg. 9 para. 3-4). Applicant’s arguments are drawn to references failing to teach this new limitation. However, this new limitation is addressed in the new rejection.
Applicant argues that the instant specification at pg. 25 discloses that having insulin complexed with a first delivery vehicle in a fibrin gel gave better release kinetics compared to when insulin is just released from the gel alone making it a more suitable means to locally deliver insulin for extended time (Remarks pg. 9 para. 5). However, this argument was not found to be persuasive, since Han teaches that when insulin is complexed with PLGA microparticles in a fibrin gel there is sustained release of the insulin compared to fibrin gel containing just insulin (pg. 2300 Col. 1 para. 1).
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632