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 .
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 is amended. Claims 1-3, 5-6, and 8-10 are being examined on the merits in this office action.
Claim Rejections - 35 USC § 103 - New
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.
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] 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).
Regarding the particle size, 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). Further Toledano teaches microcapsules comprising an active agent and a polymeric agent such as sodium alginate ([0078]; Abstract). Toeldano teaches particle size diameter1-50 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 encapsulate the CGRP with a polymer such as alginate because Kawashima teaches that the such a system helps to improve oral mucosal delivery of calcitonin derivatives (Abstract). 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, since Belhaj and Toledano teaches modifying the polymer to arrive to particle sizes that include 10 nm. 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 because Southard teaches that it helps with controlled release formulation and that the circulating plasma levels of CGRP are sufficient to maintain hemodynamic stability, thereby preventing or delaying exacerbation HF symptoms [0014] and Kawashima teaches that it improved intestinal absorption due to the prolonged residence of the nanospheres in the small intestine (Page 81, left col, last sentence).
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 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].
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.
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) [0039].
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, see Applicant arguments, filed 09/24/2025, with respect to the rejection(s) of claim(s) 1-3, 5-6, 8-10 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Belhaj and Toledano.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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