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 .
Detailed Action
Claims 1-20 are pending in this application and are now under consideration for examination.
Priority
Applicants’ claim for the benefit of priority under 35 U.S.C. 119(e) is acknowledged. This application claims benefit of Provisional application: 63/613,160 filed on 12/21/2023.
Information disclosure statement
The information disclosure statement (IDS) submitted on 07/29/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS statement is considered and initialed by the examiner.
Claim Rejections: 35 USC § 102 (AIA )
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
I. Claims 1-4, 6, 9, and 11-19 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Muhamed1 et al., (US 11,786,477 B2; priority 12/03/2018), when given the broadest reasonable interpretation.
Claims 1-4, 6, 9, and 11-18 are directed to a colloidal mixture, comprising: fibrin nanoparticles; a blood co-factor; thrombin; and a calcium salt; wherein the blood co-factor comprises whole blood, plasma, fibrinogen /thrombin, or a combination thereof; wherein the blood co-factor comprises platelet-poor plasma, platelet-rich plasma; wherein the calcium salt comprises CaCl2, method of making and method of use (as in claims 1-4, 6, 11 and 14-19); wherein the fibrin nanoparticles are present at a concentration from 0.1–250 mg/ml (as in claim 9); wherein the therapeutic agent comprises an antibiotic, antifungal, analgesic, growth factor (as in claims 12-13).
Regarding claims 1-4, 6 and 14-19, Muhamed1 et al., (US 11,786,477 B20) disclose a colloidal mixture, comprising: fibrin nanoparticles; a blood co-factor; thrombin; and a calcium salt; wherein the blood co-factor comprises whole blood, plasma, fibrinogen /thrombin, or a combination thereof; wherein the blood co-factor comprises platelet-poor plasma, platelet-rich plasma; 4wherein the calcium salt comprises CaCl2, method of making and method of use; see Abstract; entire document and certain relevant sections reproduced below:
Col. 14, lines 8-15
Disclosed herein are methods for preparing the particles disclosed above. Generally speaking, the particles can be prepared by applying a shear force to a composition of water and fibrin. The fibrin may be obtained by combining fibrinogen with thrombin. This material may be designated thrombin-polymerized fibrin. Generally, no exogenous Factor XIII or non-biological crosslinking agent (e.g., glutaraldehyde) is be added to the fibrinogen/thrombin mixture;
Col. 5, lines 4-col. 6, lines 1-65; Col. 15, lines 45-67 to col. 16, lines 1-30
Either of the continuous or dispersive streams can include additional agents, such as one or more therapeutic agents, surfactants, antioxidants, hydrogels, thickeners, etc
The dispersive and/or continuous phase may also include one or more therapeutic agents, such as described above, hi certain embodiments, the therapeutic agent will be encapsulated by the fibrin as the particle is formed. This can be achieved by including the therapeutic agent in the dispersive phase. The therapeutic agent may be freely combined with water, fibrinogen, and thrombin (along with any other desired components). In other embodiments, the therapeutic agent may be conjugated to fibrinogen prior to treatment with thrombin, or may be conjugated to the polymerized fibrin prior to shearing into particles.
Calcium; col. 9, lines 35-38
Exemplary diluents include, but are not limited to, calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate;
Col. 16
Example 1: Human fibrinogen (1 mg/ml; depleted of plasminogen, von Willebrand factor and fibronectin, FIB3, Enzyme Research Laboratories, South Bend, Ind.) was reacted with 0.5 U/ml human a thrombin (HT 1002a, Enzyme Research Laboratories, South Bend, Ind.) in HEPES buffer (25 mM HEPES, 150 mM NaCl, 5 mM CaCl2
Regarding claims 6, 9 and 12-13, Muhamed1 et al., (US 11,786,477 B20) disclose fibrin nanoparticles are present at a concentration from 0.1–250 mg/ml; further comprising a therapeutic agent… wherein the therapeutic agent comprises an antibiotic, antifungal, analgesic, growth factor; see certain relevant sections reproduced below:
Col. 4, lines 1-47
Disclosed herein are particles comprising polymerized fibrin. The particles have diameters in the nanometer to micrometer range. In some instances, the lyophilized particles have a density no greater than 100 mg/ml, no greater than 50 mg/ml, no greater than about 25 mg/ml, no greater than about 10 mg/ml, no greater than about 5 mg/ml, no greater than about 2.5 mg/ml, no greater than about 1.0 mg/ml, no greater than about 0.5 mg/ml, or no greater than about 0.1 mg/ml. In some instances, the particles can have a density between about 0.1-25 mg/ml between about 0.1-10 mg/ml, between about 0.1-5 mg/ml, between about 0.1-1.0 mg/ml, between 1-10 mg/ml, or between about 1-5 mg/ml. In some instances, the particles can have a density from 0.1-100 mg/ml, from 0.1-50 mg/ml, from 0.1-25 mg/ml, from 0.1-10 mg/ml, from 0.1-5 mg/ml, from 0.5-10 mg/ml, or from 0.5-5 mg/ml.
In some embodiments, the hydrated particles can have an average particle size no greater than about 10,000 nm, no greater than about 5,000 nm, no greater than about 2,500 nm, no greater than about 1,000 nm, no greater than about 750 nm, no greater than about 500 nm, or no greater than about 250 nm. In some embodiments, the particles can have an average particle size between about 100-10,000 nm, between about 100-5,000 nm, between about 100-2,500 nm, between about 250-2,500 nm, between about 500-2,500 nm, between about 1,000-2,500 nm, between about 100-1,500 nm, between about 100-1,000 nm, between about 100-750 nm, between about 100-500 nm, or between 100-250 nm. In yet further embodiments, the inventive particles can have an average particle size no greater than 500 μm, no greater than 250 μm, no greater than 100 μm, no greater than 75 μm, no greater than 50 μm, no greater than 25 μm, no greater than 10 μm, no greater than 5 μm, no greater than 1 μm, no greater than 0.75 μm, no greater than 0.5 μm, no greater than 0.25 μm, no greater than 0.1 μm, no greater than 0.05 μm, no greater than 0.025 μm, or no greater than 0.01 μm. In certain embodiments, the particles can have an average particle size from 0.01-100 μm, from 0.025-100 μm, from 0.05-100 μm, from 0.1-100 μm, from 0.25-100 μm, from 0.50-100 μm, from 0.75-100 μm, from 1-100 μm, from 5-100 μm, from 10-100 μm, from 25-100 μm, from 50-100 μm, from 0.01-50 μm, from 0.01-25 μm, from 0.01-10 μm, from 0.01-5 μm, from 0.01-2.5 μm, from 0.01-1 μm, from 0.01-0.75 μm, from 0.01-0.5 μm, from 0.01-0.25 μm, from 0.01-0.1 μm, from 0.05-1 μm, from 0.075-1 μm, from 0.1-1 μm, from 0.25-1 μm, from 0.5-1 μm, from 50-500 μm, from 100-500 μm, from 250-500 μm.
Col. 6, lines 15-41
In some cases, the therapeutic agent can include at least one growth factor, cytokine, chemokine, cluster differentiation (CD) antigen, neutrophin, hormone, enzyme, viral antigen, bacterial antigen, recombinant protein, natural protein, monoclonal antibody, polyclonal antibody, donor blood serum protein, donor blood plasma protein, or small molecule drug. Exemplary growth factors include keratinocyte growth factor (KGF), platelet derived growth factor (PDGF), transforming growth factor-beta (TGF.sub.β), interleukin, activin, colony stimulating factor, connective tissue growth factor (CTGF), epidermal growth factor (EGF), Epigen, erythropoietin, fibroblast growth factor (FGF), galectin, hepatoma-derived growth factor (HDGF), hepatocyte growth factor, insulin-like growth factor binding protein (IGFBP), insulin-like growth factor, insulin, leptin, macrophage migration inhibitory factor, melanoma inhibitory factor, myostatin, noggin, nephroblastoma, overexpressed (NOV), omentin, oncostatinM, osteopontin, osteoprotogerin (OPG), periostin, placenta growth factor, placental lactogen, prolactin, RANK ligand, retinol binding protein, stem cell factor, transforming growth factor, and vascular endothelial growth factor (VEGF). This includes associated isoforms from these growth factor families. In certain preferred embodiments, the particles described in the above paragraphs can include KGF, interleukin-2 (IE-2), and/or interleukin-6 (IL-6)
Hence, Muhamed1 et al., (US 11,786,477 B2; priority 12/03/2018) is deemed to anticipate claims 1-4, 6, 9, and 11-19 of the instant application, when given the broadest reasonable interpretation.
II. Claims 1-4, 6, 9, and 11-19 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Muhamed2 et al., (ACS Appl Mater Interfaces, 2019, Vol. 11(4): 3771-3780; priority 01/30/2019), when given the broadest reasonable interpretation.
Muhamed2 et al., (ACS Appl Mater Interfaces, 2019, vol. 11(4): 3771-3780; priority 01/30/2019) disclose colloidal fibrin nanoparticles comprising human fibrinogen, human a-thrombin, CaCl2, i.e., “Fibrin nanoparticles coupled with keratinocyte growth factor enhance dermal wound healing rate”; applicants are directed to following sections in Muhamed2 et al., (ACS Appl Mater Interfaces, 2019, vol. 11(4): 3771-3780; priority 01/30/2019): see Abstract; Introduction, page 2-3; last ¶, page 5; Synthesis of fibrin nanoparticle, 0.5 U/ml of human a-thrombin, 5 mM CaCl2; ¶ 2, page 5; in vivo analysis of wound healing, ¶ 2, page 8; Discussion & Conclusions, pages 13-14.
Hence, Muhamed2 et al., (ACS Appl Mater Interfaces, 2019, Vol. 11(4): 3771-3780; priority 01/30/2019) is deemed to anticipate claims 1-4, 6, 9, and 11-19 of the instant application, when given the broadest reasonable interpretation.
Since the Office does not have the facilities for examining and comparing applicants’ nanogel of the instant invention with the nanogel of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed product and method of the instant invention and the product and the method of the prior art (i.e., that the nanogel of the prior art does not possess the same material structural and functional characteristics of the nanogel of the instant invention). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
Claim Rejections: 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 1-20 are rejected under 35 U.S.C. 103(a) as being unpatentable over Muhamed1 et al., (US 11,786,477 B2) or Muhamed2 et al., (ACS Appl Mater Interfaces, 2019, Vol. 11(4): 3771-3780) as applied to claims 1-4, 6, 9, and 11-19 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above) and in view of Potier et al., (J Mater Sci., 2010, Vol 45: 2494-2503), Panwar et al., (Materialia, 2019, Vol. 7; 100373, pages 1-13), Mallis et al., (Bioeng., 2019, Vol. 6(66), pages 1-14) and Brown et al., (US 11,419,892 B2; priority 02/01/2019).
The disclosure of Muhamed1 et al., or Muhamed2 et al., as applied to claims 1-4, 6, 9, and 11-19 is described above in 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above. However, Muhamed1 et al., or Muhamed2 et al., is silent regarding wherein the calcium salt is present at a concentration from 1–1,000 µM (as in claim 5); wherein the fibrin nanoparticles comprise neonatal fibrin or equine fibrin…wherein the fibrin nanoparticles comprise cord blood fibrin (as in claims 7-8); colloidal mixture comprising the fibrin nanoparticles in an amount of 1-5,000M particles/ml, wherein the fibrin nanoparticles have an average hydrodynamic diameter from 50-1,000 nm (as in claims 10-11); and a kit comprising said nanoparticles (as in claim 20).
Regarding claim 5, wherein the calcium salt is present at a concentration from 1–1,000 µM the following references provide teaching, suggestion and motivation for determining the optimal calcium concentration as calcium determines the flow properties and clotting efficiency, the structural and functional elements of the instant invention:
Potier et al., (J Mater Sci., 2010, Vol 45: 2494-2503), provide evidence that calcium increased gel opacity and flow properties of gel and a skilled artisan can modulate the mechanical and biological properties of fibrin glues/hydrogels/nanoparticles by optimizing calcium concentration (see Abstract; Table 1, page 2495; Fig. 1, page 2497; and entire document) and Potier et al., conclude “These results demonstrated that, not only fibrinogen and thrombin, but also dilution buffers can significantly affect fibrin mechanical properties and the behavior of seeded cells. Modulating buffer composition can, therefore, constitutes an additional tool to tailor fibrin scaffolds with mechanical and biological properties appropriate for tissue engineering applications, such as bone or cartilage regeneration” (col. 1, last ¶, page 2503).
Similarly, regarding claim 5, Panwar et al., (Materialia, 2019, Vol. 7; 100373, pages 1-13), provide evidence that calcium increased gel opacity and flow properties of gel and a skilled artisan can modulate the mechanical and biological properties of fibrin glues/hydrogels/nanoparticles by optimizing calcium concentration (see Abstract; ¶ 2.8, page 3; Scheme 1, page 4; Fig. 4, page 7; Fig. 6-7, pages 9-10; and entire document).
Regarding claims 7-8, wherein the fibrin nanoparticles comprise neonatal fibrin or equine fibrin…wherein the fibrin nanoparticles comprise cord blood fibrin, Mallis et al., (Bioeng., 2019, Vol. 6(66), pages 1-14) advantageously teach fibrin gel derived from cord blood play a significant role in wound healing and a standardized production process of said fibrin gels (see Abstract; and entire document).
Regarding claims 10-11 and 20, Brown et al., (US 11,419,892 B2; priority 02/01/2019) teach colloidal mixture comprising the fibrin nanoparticles in an amount of 1-5,000M particles/ml, wherein the fibrin nanoparticles have an average hydrodynamic diameter from 50-1,000 nm; and a kit comprising said nanoparticles (see Abstract; col. 8, lines 31-60; and entire document); said reference ultra-low crosslinked polymer can have a hydrodynamic radius, in the collapsed state, from 0.05-20 μm,… microgels disclosed herein can have a volume in the hydrated state that is between 0.05-50 μm (col. 5, lines 33-45); including number of nanoparticles per unit volume of microgel such as 5 ng-10, 000 ng/gram of microgel (col. 6, lines 18-45). Furthermore, it would have been obvious to one of ordinary skill in the art to make a kit comprising said nanoparticles for various applications in pharmaceutical and other allied industries. One of skill in the art is motivated to place said components in a kit for the benefit of having all the necessary ingredients together to carry out the desired reaction, thus reducing the amount of time required to carry out the desired reaction. One of ordinary skill in the art would have had a reasonable expectation of success, as Brown et al., (US 11,419,892 B2; priority 02/01/2019) have disclosed a kit comprising said nanoparticles.
Therefore, it would have been obvious to a person of ordinary skill in the art to combine and modify the teachings of Muhamed1 et al., or Muhamed2 et al., and employ the optimal calcium salt is present at a concentration from 1–1,000 µM depending on experimental need and flow properties of the colloidal nanoparticles as suggested in the teachings of Potier et al., and Panwar et al., including the use of fibrin gel derived from cord blood as suggested in the teachings of Mallis et al., and said combined references also provide the structural and functional elements involved in the production of a colloidal mixture, comprising: fibrin nanoparticles; a blood co-factor; thrombin; and a calcium salt; wherein the blood co-factor comprises whole blood, plasma, fibrinogen /thrombin, or a combination thereof; wherein the blood co-factor comprises platelet-poor plasma, platelet-rich plasma; wherein the calcium salt comprises CaCl2, method of making and method of use and adopt the methods of Brown et al., and to produce the same in a kit form. Motivation to generate such a kit derives from the fact that placing said components in a kit for the benefit of having all the necessary ingredients together to carry out the desired reaction, thus reducing the amount of time required to carry out the desired reaction. The expectation of success is high, because the combined teachings Muhamed1 et al., or Muhamed2 et al., Potier et al., Panwar et al., Mallis et al., and Brown et al., teach the structural and functional elements of the instant invention (Teaching, Suggestion and Motivation).
Given this extensive teaching in prior art (Muhamed1 et al., or Muhamed2 et al., Potier et al., Panwar et al., Mallis et al., and Brown et al.,) i.e., a colloidal mixture, comprising: fibrin nanoparticles; a blood co-factor; thrombin; and a calcium salt; wherein the blood co-factor comprises whole blood, plasma, fibrinogen /thrombin, or a combination thereof; wherein the blood co-factor comprises platelet-poor plasma, platelet-rich plasma; wherein the calcium salt comprises CaCl2, method of making and method of use, as taught by the instant invention and as claimed in claims 1-20 is not of innovation but of ordinary skill in the art and the expectation of success is extremely high i.e., “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”KSR, 550 U.S. at, 82 USPQ2d at 1397”.
Therefore, claims 1-20 are rejected under 35 U.S.C. 103(a) as being unpatentable over Muhamed1 et al., (US 11,786,477 B2) or Muhamed2 et al., (ACS Appl Mater Interfaces, 2019, vol. 11(4): 3771-3780) as applied to claims 1-4, 6, 9, and 11-19 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) rejection above) and in view of Potier et al., (J Mater Sci., 2010, Vol 45: 2494-2503), Panwar et al., (Materialia, 2019, Vol. 7; 100373, pages 1-13), Mallis et al., (Bioeng., 2019, Vol. 6(66), pages 1-14) and Brown et al., (US 11,419,892 B2; priority 02/01/2019).
Allowable Subject Matter/Conclusion
None of the claims are allowable.
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/GANAPATHIRAMA RAGHU/ Primary Examiner, Art Unit 1652
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