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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/15/2026 has been entered.
Priority
This application was filed on and is a U.S. national Stage application under 35 U.S.C. 371 of International Patent Application No. PCT/US2020/044407 filed 07/31/2020, which claims the benefit of the priority of US Provisional application 62/880723 filed 07/31/2019.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
It is noted that Applicants have not filed an information disclosure statement under § 1.97(c). Applicant is reminded of 37 CFR § 1.56, which details Applicant’s duty to disclose all information known to be material to patentability.
Claim Status
Claims 1-3, 5-6, 8-18 are pending. Claims 1-2, and 5-6 are amended. Claims 11-18 are withdrawn. Claims 1-3, 5-6, and 8-10 are being examined on the merits in this office action.
Claim Rejections - 35 USC § 103 – Maintained and Modified
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim Interpretation
Examiner is interpretating claim 1 as a product claim, wherein the product is a delivery system that comprises at least one α-CGRP and at least one alginate polymer, wherein the CGRP peptide is encapsulated in the alginate polymer.
Examiner notes the limitation is claim 1 “…wherein a delivery system time of release is tunable via varying an alginate polymer content encapsulating the α-CGRP and irradiating the at least one alginate polymer to vary stiffness of the alginate polymer content encapsulating the α-CGRP to arrive at a pre-selected dosage of the at least one α-CGRP delivered over an extended period of time and wherein the at least one α-CGRP peptide is encapsulated via electrospray method to produce microcapsules ” recites a product-by-process limitation. Examiner notes that the patentability of a product does not depend on its method of production. Thus, the patentability is based on the product itself. Therefore, prior art that teaches a delivery system that comprises at least one α-CGRP and at least one alginate polymer would read on claim 1.
Further, Examiner is interpreting α-CGRP to include both native and modified α-CGRP. This is supported by the disclosure on Page 26, line 21, Page 30, line 12-13 wherein α-CGRP includes α-CGRP and its derivatives. Further, Page 56, line 10 discloses the sequence of the instant α-CGRP. Thus a reference that teaches modified α-CGRP or α-CGRP with the same sequence disclosed in the instant invention, would read on the recited α-CGRP.
Additionally, the instant claims recites “…sodium alginate having high mannuronic acid content and low viscosity” in claim 1. The instant disclosure defines such sodium alginate as a solution comprising 2% alginic acid (See Specification Page 16 and Page 35). Examiner notes a reference that discloses 2% alginic acid or sodium alginate would read on sodium alginate having high mannuronic acid content and low viscosity.
Claims 1-3, 5-6, 8-10 are still rejected under 35 U.S.C. 103 as being unpatentable over Southard et al. (US20110150980A1 – hereinafter “Southard”) in view of Kawashima et al. (Pharmaceutical Development and Technology, 5(1), 77–85 (2000)), Belhaj (https://scholarcommons.sc.edu), and Toledano et al. (US20180207451A1 – hereinafter “Toledano”).
Southard teaches a delivery system that comprises a calcitonin gene related peptide (CGRP) and a biodegradable polymer (claims 1-2; [0002-0005, 0008, 0010, 0042-0046]), that the peptide can be the alpha CGRP [0003, 0057, 0061, 0128]. Southard further teaches sustained release delivery systems, comprising the peptide or peptide-like analogs of CGRP [0008, 0040] and that the sequence of the sequence modified calcitonin gene related peptide (CGRP) includes SEQ ID NO: 4 [0010, 0040] which is identical to the instant SEQ ID NO: 1. Southard teaches that the CGRP is trapped or encapsulated within the polymeric matrix [0241, 0244, 0281], and that the invention further provides methods of treating a patient comprising administering sequence modified CGRP to the patient such that circulating plasma levels of sequence modified CGRP are sufficient to maintain hemodynamic stability, thereby preventing or delaying exacerbation of symptoms [0257, 0336]. Southard teaches the delivery system for sustained and controlled release of the peptide (claims 4, 11, 15; [0008, 0041-0044]), wherein the amounts of the polymer and the solvent are effective to form the polymer matrix comprising sequence modified CGRP in situ when the formulation contacts the bodily fluid tissue or fluid [0040]. Southard teaches that the release of sequence modified CGRP from the solid polymer matrices (implants) will follow the same general rules for release of a drug from a monolithic polymeric device. The release of sequence modified CGRP can be affected by the size of the implant (i.e., the amount of polymer composition administered to the patient), the loading of sequence modified CGRP within the implant, the permeability factors involving sequence modified CGRP and the particular polymer, and the degradation of the polymer. Depending upon the amount of sequence modified CGRP selected for delivery, the above parameters can be adjusted by one skilled in the art of drug delivery to give the desired rate and duration of release. Thus, the flowable composition can be designed to produce an implant that will release sequence modified CGRP over a targeted period from days to months [0255]. Southard teaches that the release of sequence modified CGRP can be affected by the size and shape of the polymer matrix, the loading of drug within the polymer matrix, the permeability factors involving sequence modified CGRP and the particular polymer, and the degradation of the polymer. The above parameters can be adjusted by one skilled in the art of drug delivery to give the desired rate and duration of release [0266]. Further, Southard teaches particle size as small as less than 50 nm [0294].
Southard does not teach the biodegradable polymer is the alginate polymer.
Kawashima teaches the use of mucoadhesive PLGA nanosphere system to improve oral mucosal delivery of calcitonin derivatives, e.g., elcatonin, in rats by coating the surface of the nanospheres with a mucoadhesive polymer and that the Elcatonin-encapsulated PLGA nanospheres is coated with mucoadhesive polymer, such as poly(acrylic acid), sodium alginate, and chitosan (page 79, left col. 3rd paragraph, line 1-11).
Additionally, Belhaj teaches alginate microcapsules and teaches the use of the electrospray method to encapsulate peptides and proteins and that a second coating of poly-l-ornithine (PLO) polymer can be used to increase the integrity of alginate microcapsules (Page v, “Abstract)1st paragraph). Belhaj teaches that the properties of the microcapsule size are controlled by different parameters such as applied voltage, spraying distance, flow rate, method of encapsulation, and polymer concentration (page 2, line 1-4). Belhaj teaches that the parameters of 60mm/h flow rate and 8.0 kV voltage were adjusted to produce microcapsules size of ~150 µm(Page 44, line 15-16) or constant parameters of 60mm/hr flow rate and 6.0kV initial voltage were adjusted to produce microcapsules size of ~200 µm (Page 25, line 3-7). Belhaj teaches that the microencapsulation was done with 2% alginate solution while the CaCl2 gelling bath was synthesized at 0.15M CaCl2 (Page 16, last paragraph, line 1-8, line; Page 24, 2nd paragraph, line 1-7). Examiner notes that this amount of sodium alginate contains a high mannuronic acid content and low viscosity. Thus this limitation is met. Belhaj teaches a gelling bath that contains calcium chloride which forms a coating to the microcapsule (Page 24, 2nd paragraph, line 7-14, Page 44, line 5-13). Belhaj teaches the use of crosslinker to increase the stiffness of the microcapsule in order for the microcapsules to maintain their shape (Page 17, line 1-2). Belhaj teaches that the goal of encapsulation is to serve as a drug delivery tool, sustained release of therapeutics from encapsulated cells, and regenerative medicine tool, delivering cells to particular tissues (Page 22, line 8-10).
Further Toledano teaches microcapsules comprising an active agent and a polymeric agent such as sodium alginate ([0078]; Abstract). Toeldano teaches particle size diameter 1-50 nm or 5-30 nm[0073].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Southard with the teachings of Kawashima and Belhaj and encapsulate the CGRP with a polymer such as sodium alginate because Kawashima teaches that the such a system helps to improve oral mucosal delivery of calcitonin derivatives (Abstract) and Belhaj teaches that the use of sodium alginate to encapsulate therapeutics serves as a drug delivery tool for sustained release of the therapeutics (Page 22, line 8-10). It would have been obvious to modify Southard with the teachings of Belhaj and Toledano and modify the alginate polymer and electrospray method to arrive to a microparticle as small as 10 nm or ~200 µm, since Belhaj and Toledano teaches modifying the polymer to arrive to particle sizes that include 10 nm and ~200 µm. One of ordinary skill in the art would be motivated and would have had a reasonable expectation of success in preparing such a delivery system that encapsulated CGRP with sodium alginate because Belhaj teaches that sodium alginate is a natural polymers and it is used widely in microcapsule formation because of its unique properties including low toxicity, biocompatibility, mechanical stability, bioadhesive properties, gelling properties and abundance (Page 3, whole of last paragraph).
Examiner further notes that the limitation “…wherein a delivery system time of release is tunable via varying an alginate polymer content encapsulating the α-CGRP and irradiating the at least one alginate polymer to vary stiffness of the alginate polymer content encapsulating the α-CGRP to arrive at a pre-selected dosage of the at least one α-CGRP delivered over an extended period of time and wherein the at least one α-CGRP peptide is encapsulated via electrospray method to produce microcapsules ” recites a product-by-process limitation.
Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” See MPEP § 2113. Claim 1 is drawn to delivery system for maintaining peptide levels in plasma comprising: at least one a-calcitonin gene regulated peptide (a-CGRP); at least one alginate polymer, wherein the at least one a-CGRP is encapsulated in the at least one alginate polymer to form at least one alginate-a-CGRP; and wherein a delivery system time of release is tunable via varying an alginate polymer content encapsulating the a-CGRP and irradiating the at least one alginate polymer to vary stiffness of the alginate polymer content encapsulating the a-CGRP to arrive at a pre-selected dosage of the at least one a-CGRP delivered over an extended period of time; and wherein the at least one a-CGRP peptide is encapsulated via an electrospray method to produce microcapsules. The substance and structure of the claimed delivery system is not affected by this limitation, which merely reflects one version of a process that could be used to make the product. The delivery system could be made in other ways, thus, the limitation “wherein a delivery system time of release is tunable via varying an alginate polymer content encapsulating the a-CGRP and irradiating the at least one alginate polymer to vary stiffness of the alginate polymer content encapsulating the a-CGRP to arrive at a pre-selected dosage of the at least one a-CGRP delivered over an extended period of time; and wherein the at least one a-CGRP peptide is encapsulated via an electrospray method to produce microcapsules…” does not add patentable weight to the claim. If the product in this claim is the same as or obvious from a product of the prior art, the claim is unpatentable. The delivery system comprising CGRP and alginate is clearly disclosed in the prior art (Southard teaches delivery system comprising CGRP and a biodegradable polymer. Kawashima teaches such a system comprising calcitonin derivative and alginate polymer) thus claim 1 is rejected as unpatentable over Southard, Belhaj, and Kawashima.
Regarding claim 2, Southard teaches that the method helps in delivering CGRP for a time and at a dose effective to provide symptomatic relief, prevent exacerbation of symptoms, and/or prevent and/or delay progression of the disease state of heart failure in said patient [0041]. Southard teaches that the invention provides a method of treating patients comprising administering CGRP to the patient such that circulating plasma levels of CGRP are sufficient to maintain hemodynamic stability, thereby preventing or delaying exacerbation symptoms [0336]. Additionally, Belhaj teaches delayed release up to day 6 (Page 17, last 3 lines). Further, Examiner notes that the instant delivery system has been rendered obvious by the cited references and that the limitation of the number of days the delivery system releases the a-CGRP is an expected result. Further, MPEP 2111.04 states: claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In the instant case, the limitation expresses the intended result of the method step of claim 1 and is given little patentable weight.
Regarding claim 3, Southard teaches that CGRP encapsulated in the microparticle must be released from the microparticle before traveling through the gel matrix and entering the biological system and that the immediate release, or the burst, associated with microparticle delivery systems can be reduced and modulated. Since the release rates of CGRP from these two systems can be quite different, embedding microparticles in the gel phase offers additional modulation and economical use of CGRP and that the benefits include higher bioavailability and longer duration of action than either system when used alone [0291].
Regarding claim 5, Southard teaches a miniature drug-dispensing system that operates like a miniature syringe and releases minute quantities of concentrated sequence modified CGRP formulations in a continuous, consistent flow over months or years [0315]. Examiner notes that this particular teaching reads on the CGRP remaining stable since there is an expectation that a composition that is being administered over months or years has to be stable for it to have the therapeutic effect, rendering obvious claim 5. Additionally, Belhaj teaches that the microcapsules were rehydrated using deionized water and tested morphologically to ensure complete recovery and shape retaining (Page 14, 2nd paragraph, line 6-7; Page 17, 2nd paragraph, line 1-2).
Regarding claim 6, Southard teaches that the CGRP system was found to produce profoundly beneficial hemodynamic responses including increased cardiac output, decreased ventricular filling pressures, pulmonary and systemic arterial pressures [0261]. Southard teaches that the "pulmonary artery pressure" (PA pressure) refers to blood pressure in the pulmonary artery [0109]. It would have been obvious to prepare a delivery system comprising CGRP and a biodegradable polymer such as alginate to lower blood pressure since Southard teaches that sequence modified CGRP has unexpected improved activity compared to native CGRP (Example 1) in reducing mean arterial pressure (MAP), diastolic Blood pressure (DBP) and systolic blood pressure (SBP) (Table 1; [0039]). Examiner notes that the instant delivery system has been rendered obvious by the cited references and that the limitation “up to 18 hours to 3 days..” is an expected result. Further, MPEP 2111.04 states: claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In the instant case, the limitation expresses the intended result of the method step of claim 1 and is given little patentable weight.
Regarding claim 8, Kawashima teaches the use of mucoadhesive PLGA nanosphere system to improve oral mucosal delivery of calcitonin derivatives, e.g., elcatonin, in rats by coating the surface of the nanospheres with a mucoadhesive polymer and that the Elcatonin-encapsulated PLGA nanospheres is coated with mucoadhesive polymer, such as poly(acrylic acid), sodium alginate, and chitosan (page 79, left col. 3rd paragraph, line 1-11). It would have been obvious to prepare a delivery system comprising CGRP and a biodegradable polymer such as alginate that comprises sodium-alginate.
Regarding claim 9, Southard teaches that the CGRP or a pharmaceutically acceptable formulation thereof may be formulated for parenteral administration, e.g., for intravenous, subcutaneous, or intramuscular injection [0239]. It would have been obvious to prepare a delivery system comprising CGRP and a biodegradable polymer such as alginate for administration including subcutaneous administration.
Regarding claim 10, Southard teaches that the CGRP analogs [0008, 0079, 0140, 0181] and CGRP agonist analogs [0091, 0397].
Response to Arguments
Applicant's arguments filed 04/15/2026 have been fully considered but they are not persuasive.
Applicant Arguments
Applicant argues that the cited references do not teach the new added limitations such as "at least one alginate polymer comprising sodium alginate having high mannuronic acid content and low viscosity,", "to form at least one alginate-a-CGRP microcapsule comprising a Ca+2-coated alginate matrix,", "a size in a range from 10 nm to 500 pm", "voltage, flow rate, and distance between a needle and a gelling bath solution.". applicant argues that the pecification describes these features expressly. See, e.g., pages 16-18 (sodium alginate with high mannuronic acid content and low viscosity; 150 mM CaCl2 gelling bath; 6 kV voltage; 60 mm/hr flow rate; 7 mm distance; Ca+2-coated alginate-a-CGRP microcapsules), and page 26 (electrospray-produced capsules ranging from 10 nm to 500 pm by adjusting voltage, flow rate, and needle-to-bath distance).
Applicant further argues that Southard, Kawashima, Belhaj and Toledano do not teach the instant limitations.
Applicant further argues that the office action provides no persuasive, factually supported reason why a person of ordinary skill in the art would have replaced Southard's polymer matrix and implant teachings with the specific electrosprayed, Ca+2-crosslinked, high-mannuronic, low-viscosity sodium alginate microcapsule system now claimed.
Applicant argues that the proposed combination is a classic hindsight reconstruction, assembled only with Applicant's disclosure as a roadmap (Page 7-10 of Arguments).
Applicant further argues that the cited references do not teach the limitations of the dependent claims (Page 10-11 of Arguments
Examiner’s Response
The arguments presented above have been fully considered but are unpersuasive. Examiner notes that it is known in the art as taught by Southard, that CGRP peptide has a short half-life in the blood serum, and that administering sequence modified CGRP trapped or encapsulated within the polymeric matrix to the patient is such that circulating plasma levels of sequence modified CGRP are sufficient to maintain hemodynamic stability, thereby preventing or delaying exacerbation of symptoms [0257, 0336]. Thus, encapsulating CGRP peptide with a polymer is known in the art and recommended for sustained release of the peptide. Examiner notes that sodium alginate is another type of polymer that is known to be used to encapsulate peptide drugs. The method of using electrospraying to encapsulate peptide drugs with sodium alginate is known in the art as taught by Belhaj. Belhaj teaches that the microencapsulation was done with 2% alginate solution while the CaCl2 gelling bath was synthesized at 0.15M CaCl2 (Page 16, last paragraph, line 1-8; Page 24, 2nd paragraph, line 1-7). Examiner notes that this amount of sodium alginate contains a high mannuronic acid content and low viscosity. Thus this limitation is met. Belhaj teaches a gelling bath that contains calcium chloride which forms a coating to the microcapsule (Page 24, 2nd paragraph, line 7-14, Page 44, line 5-13). Additionally, Belhaj teaches alginate microcapsules and teaches the use of the electrospray method to encapsulate peptides and proteins and that a second coating of poly-l-ornithine (PLO) polymer can be used to increase the integrity of alginate microcapsules (Page v, “Abstract)1st paragraph). Belhaj teaches that the properties of the microcapsule size are controlled by different parameters such as applied voltage, spraying distance, flow rate, method of encapsulation, and polymer concentration (page 2, line 1-4). Belhaj teaches that the parameters of 60mm/h flow rate and 8.0 kV voltage were adjusted to produce microcapsules size of ~150 µm (Page 44, line 15-16) or constant parameters of 60mm/hr flow rate and 6.0kV initial voltage were adjusted to produce microcapsules size of ~200 µm (Page 25, line 3-7). Examiner notes that Belhaj teaches the exact instant method of electrospraying with the same instant concentrations. Applicant argument that the cited references do not teach the instant limitations is unpersuasive.
Further, Applicant argument that the rejection provides no persuasive, factually supported reason why a person of ordinary skill in the art would have replaced Southard's polymer matrix and implant teachings with the specific electrosprayed, Ca+2-crosslinked, high-mannuronic, low-viscosity sodium alginate microcapsule system now claimed, is unpersuasive. Examiner notes that Belhaj provides the motivation for using sodium alginate to encapsulate therapeutic drugs. Specifically, Belhaj teaches that the goal of encapsulation is to serve as a drug delivery tool, sustained release of therapeutics from encapsulated cells, and regenerative medicine tool, delivering cells to particular tissues (Page 22, line 8-10). Additionally, Belhaj already teaches electrosprayed, Ca+2-crosslinked, high-mannuronic, low-viscosity sodium alginate microcapsule. Belhaj teaches that sodium alginate is a natural polymers and it is used widely in microcapsule formation because of its unique properties including low toxicity, biocompatibility, mechanical stability, bioadhesive properties, gelling properties and abundance (Page 3, whole of last paragraph). One of ordinary skill in the art who has read Belhaj would be motivated to modify Southard and use sodium alginate as the polymer to encapsulate a-CGRP for controlled release. Examiner notes that the cited references teach all the recited limitations of the claimed invention. This argument is unpersuasive.
Regarding Applicant of hindsight reasoning, Examiner is not convinced. Examiner notes that "[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." (MPEP 2145 (X)(A). In the instant case, a delivery system comprising a-CGRP and a polymer was already known in the art as taught by Southard. The use of sodium alginate to encapsulate peptide drugs was also already known in the art as taught by Kawashima and Belhaj. One of ordinary skill in the art would simply be motivated to use another type of polymer such as sodium alginate since Belhaj teaches that sodium alginate is a natural polymers and it is used widely in microcapsule formation because of its unique properties including low toxicity, biocompatibility, mechanical stability, bioadhesive properties, gelling properties and abundance (Page 3, whole of last paragraph). The arguments are unpersuasive.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mercy H. Sabila whose telephone number is (571)272-2562. The examiner can normally be reached Monday - Friday 5:00 am - 3:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MERCY H SABILA/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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