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 .
The examiner acknowledges receipt of preliminary amendment filed 06/15/2023 and IDS filed 10/11/2023, 08/08/2023 and 06/15/2023.
Claims 1-28 are amended.
New claim 29 is added.
Claims 1-29 are pending.
Priority
This application is a 371 of PCT/EP2021/086316 filed 12/16/2021 and which claims benefit of 63/126,125 filed 12/16/2020.
Information Disclosure Statement
The IDS filed 10/11/2023, 08/08/2023 and 06/15/2023 has been considered by the examiner.
Specification
Objections to the Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. The specification at page 3, line 5 has embedded hyperlink. Correction is requested.
The disclosure is objected to because of the following informalities: Drawings have been filed in this application. However, “Brief description of the several view of the drawing” is missing. MPEP 608.01()a) Arrangement of Application [R-07.2022] requires that in the case where drawings are filed, the specification should include a section on ---Brief description of the several views of the drawing---.
Appropriate correction is required.
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 3-5, 7-9, 11-14 and 23 and 28 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.
Regarding claim 3, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 4-5, 7-9, 11-14 and 23 use the term “preferably” to narrow volume of a pharmaceutical composition (claim 4); narrow organic solvent (claim 5); narrow the ratio of P1R4 to dP2R3 (claim 7); narrow the amount of triblock copolymer (claims 8 and 9); narrow the amount of diblock copolymer (claim 11); narrow the amount of triblock and deblock copolymers (claims 12 and 13); narrow the amount of DMSO (claim 14); narrow the volume in the prefilled syringe (claim 23). Thus, claims 4-5, 7-9, 11-14 and 23 recite broad recitations followed by narrower statement recitations of the range/limitation in the same claims. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
For claims 7 and 28, the claims have recited “P1R4” and “dP2R3” without initial description of what these abbreviations are. Table 3a of the specification as filed has identified “P1R4” as a triblock copolymer and “dP2R3” as a diblock copolymer. Based on this, “P1R4” and “dP2R3” are examined as triblock copolymer and diblock copolymer.
Correction is requested.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by de Melo Guilherme Dias et al., “Anti-Covid-19 efficacy of ivermectin in the golden hamster” in bioRxiv, 22 November 2020 (submitted by applicant in an IDS).
Claim 1 prophylactically treats COVID-19 in a subject at high risk for exposure to SARS-CoV-virus or who has recently been exposed to SARS-CoV-2, the subject test negative for the virus; the method comprises administering an effective dose of ivermectin to the subject. No specific dose is recited for the effective dose such that effective dose is determined by the artisan. No specific mode of administration is recited in claim 1. It is the dose administered by the artisan to the subject that inhibits development of one or more COVID-19 symptoms.
de Melo Guilherme Dias subcutaneously injected hamster animals with 400 mg/kg of ivermectin after inoculating the hamster animals with SARS-CoV-2 (page 3, lines 5-32). Inoculating the hamsters with SARS-CoV-2 meets the limitation of “recently exposed” and “high risk for exposure” and these hamsters were negative for COVID at the time they were infected and at least at day 1 of the infection. Because it is the administered ivermectin that inhibits development, the ivermectin subcutaneously administered in de Melo Guilherme Dias also inhibits development of COVID-19. de Melo Guilherme Dias specifically states that ivermectin reduced clinical and/or prevented occurrence of anosmia, which is a typical symptom of COVID-19 (page 3, lines 30-32).
de Melo Guilherme Dias teaches all the elements of claim 1.
Claim Rejections - 35 USC § 103
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(s) 2 is rejected under 35 U.S.C. 103 as being unpatentable over de Melo Guilherme Dias et al., “Anti-Covid-19 efficacy of ivermectin in the golden hamster” in bioRxiv, 22 November 2020 (submitted by applicant in an IDS) in view of Mengmeng Lu et al., “Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation” in Drug Delivery 2017 24(1): 622-631.
de Melo Guilherme Dias subcutaneously injected hamster animals with 400 mg/kg of ivermectin after inoculating the hamster animals with SARS-CoV-2 (page 3, lines 5-32). Inoculating the hamsters with SARS-CoV-2 meets the limitation of “recently exposed” and “high risk for exposure” and these hamsters were negative for COVID at the time they were infected and at least at day 1 of the infection. Because it is the administered ivermectin that inhibits development, the ivermectin subcutaneously administered in de Melo Guilherme Dias also inhibits development of COVID-19. de Melo Guilherme Dias specifically states that ivermectin reduced clinical and/or prevented occurrence of anosmia, which is a typical symptom of COVID-19 (page 3, lines 30-32).
Claim 2 differs from claim 1 in that the ivermectin administered in claim 2 is sustained release.
de Melo Guilherme Dias does not teach delivering the ivermectin as a sustained release formulation. However, sustained release formulation of ivermectin is known and Mengmeng Lu teaches that sustained release formulations have several advantages over conventional dosage forms; the sustained release formulations provide prolonged therapeutic effect and reduce frequency of dosing (see the title, last full paragraph, right column of page 622). Therefore, before the effective date of the invention, one having ordinary skill in the art, would be motivated to administer ivermectin in the for of sustained release with the expectation that the sustained release formulation would predictably provide prolonged therapeutic effect and reduce frequency of dosing.
Therefore, de Melo Guilherme Dias in combination with Mengmeng Lu renders claim 2 prima facie obvious.
Claim(s) 3, 5-6, 8-14, 19, 22-25 and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over de Melo Guilherme Dias et al., “Anti-Covid-19 efficacy of ivermectin in the golden hamster” in bioRxiv, 22 November 2020 (submitted by applicant in an IDS) in view of Mengmeng Lu et al., “Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation” in Drug Delivery 2017 24(1): 622-631, as applied to claim 2, and further in view of ABBASSI et al. (WO 2019016234 A1).
Claims 3, 5-6, 8-14, 19, 22-25 and 27-29 depend from claim 2 directly or indirectly. Claim 3 depends on claim 2.
de Melo Guilherme Dias in combination with Mengmeng Lu has been described above to render claim 2 prima facie obvious.
For claim 3, de Melo Guilherme Dias in combination with Mengmeng Lu does not use the polymer of claim 3
ABBASSI teaches injectable sustained release composition comprising biodegradable triblock copolymer Av-Bw-Ax, where A is polyester, B is polyethylene glycol, v and x are number of repeat units ranging from 1 to 3000 and w is the number of repeat units ranging from 3 to 300 and v=x or vy-Az, where A is polyester and C is an end-capped polyethylene glycol with y and z being number of repeat units with y ranging from 2 to 250 and z ranges from 1 to 3000; and at least one active ingredient (see the whole document with emphasis on page 3, lines 11-35) and where the active agent is ivermectin (page 7, lines 2-3; page 7, lines 25; page 28, line 9; Table 5; Table 10 and claim 15). In one embodiment A is PLA (page 4, line 29; Table 5).
Therefore, before the effective date of the invention, the artisan looking to de Melo Guilherme Dias, Mengmeng Lu and ABBASSI would be motivated to use biodegradable deblock and triblock copolymers of PLA-PEG/PLA-PEG-PLA for effective sustained release of the active agent ivermectin.
For claim 5, ABBASSI teaches DMSO solvent is used (see at least page 9, lines 18-29).
For claim 6, the active agent ivermectin is present from 0.05% to 60% or 0.05% to 40%; and in further embodiment, the pharmaceutically active agent ivermectin is present at 10% to 50% or 20% to 40% or 20% to 35% (page 7, lines 5-12, 18-20 of ABBASSI) and the amount disclosed in the ranges encompass the claimed range of 16% to 25% w/w; the disclosed ranges allow for the claimed range of 16% to 25%. There is no factual showing that the claimed ranges provides unexpected results.
For claims 8 and 9, the triblock copolymer is present at 1% to 50% (w/w%) (page 7, lines 22-23 of ABBASSI); the disclosed range encompassing the claimed range of 2% to 19% (claim 8) and 2% to 8% (claim 9) with the disclosed ranges allowing for 2% to 19% and 2% to 8%. There is no factual showing that the claimed ranges provides unexpected results.
For claims 10 and 11, the diblock copolymer is present at 1% to 57% (w/w%) (page 7, lines 25-26 of ABBASSI) with the disclosed ranges encompassing the claimed ranges and allowing for 3% to 16% (claim 10) and 3% to 8% (claim 11). There is no factual showing that the claimed ranges provides unexpected results.
For claims 12 and 13 and 14, in one embodiment, formulation F328 has 10.00% triblock copolymer and 15.00% diblock copolymer and 74.00% DMSO (Figure II , page 13, lines 25-29). The total weight of 25% triblock plus diblock being a species of the claimed range of 7-28% (claim 12) and the 74% DMSO is species of the claimed range of 52-80% (claim 14). With respect to claim 13, the ordinary skilled artisan taking the teachings of ABBASSI would optimize the triblock copolymer and diblock copolymer that would predictably provide expected release of the active agent.
For claim 19, de Melo Guilherme Dias teaches that ivermectin can be administered alone or in combination with other molecules (page 2, lines 31-32; page 3, line 5; page 5, lines 13-14). ABBASSI teaches administering biodegradable drug delivery composition comprising mixture of triblock copolymer and diblock copolymer (see the whole document with emphasis on the abstract), and active agent that is ivermectin (page 6, line 34; page 7, lines 2-3). Therefore, it would be reasonable to expect that the ivermectin can be administered alone before the administration of ivermectin in mixture of triblock copolymer and diblock copolymer matrix.
For claims 22 and 23, de Melo Guilherme Dias subcutaneous injects ivermectin (page 3, line 11) and a single subcutaneous injection of 200 mL of freshly-diluted ivermectin as given (page 10, lines 24-28); de Melo Guilherme Dias does not say injection with a syringe; but it is common knowledge injection is by using syringe that is already filled with the agent of interest. 200 mL is 0.2 mL which is specific point within the claimed range of 0.1 mL to 1.5 mL as required by claim 23.
For claims 24 and 25, upper arm and abdomen are known areas of the body to receive subcutaneous injections.
For claim 27, ABBASSI teaches triblock copolymer to diblock copolymer ratio of 1:5, 1:10, 1:19, 4:1, 3:1 and 2:1 (page 26, lines 2-5).
For claim 28, ABBASSI teaches that the active agent ivermectin is present at 10% to 50% or 20% to 40% or 20% to 35% (page 7, lines 5-12, 18-20) with the disclosed range encompassing the claimed range of 16.25 to 25%; ABBASSI teaches the triblock copolymer is present at 1% to 50% (w/w%) (page 7, lines 22-23) and this range encompasses the claimed range of 8.3% and the disclosed range allowing for 8.3%; ABBASSI teaches diblock copolymer is present at 1% to 57% (w/w%) (page 7, lines 25-26) with the disclosed ranges encompassing the claimed range of 4.2% with the disclosed range allowing for 4.2%. There is no factual showing that the claimed rang of 16.25 to 25% ivermectin, 8.3% triblock copolymer and 4.2% diblock copolymer provides unexpected results.
For claim 29, ABBASSI teaches injectable sustained release composition comprising biodegradable triblock copolymer Av-Bw-Ax, where A is polyester, B is polyethylene glycol, v and x are number of repeat units ranging from 1 to 3000 and w is the number of repeat units ranging from 3 to 300 and v=x or vy-Az, where A is polyester and C is an end-capped polyethylene glycol with y and z being number of repeat units with y ranging from 2 to 250 and z ranges from 1 to 3000; and at least one active ingredient (see the whole document with emphasis on page 3, lines 11-35) and where the active agent is ivermectin (page 7, lines 2-3; page 7, lines 25; page 28, line 9; Table 5; Table 10 and claim 15). In one embodiment A is PLA (page 4, line 29; Table 5). Thus, triblock copolymer Av-Bw-Ax, would be ck copolymer PLAv-PEGw-PLAx, where v and x are number of repeat units ranging from 1 to 3000 and w is the number of repeat units ranging from 3 to 300 and v=x or vy-Az, would be MePEGy-PLAz, where y ranging from 2 to 250 and z ranges from 1 to 3000. The ranges from 2 to 250 or 3-300 for w and y contain within the range the claimed ranges and 1 to 3000 for v and x and z contain the claimed ranges.
Thus, de Melo Guilherme Dias in combination with Mengmeng Lu and ABBASSI renders claims 3, 5-6, 8-14, 19, 22-25 and 27-29
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over de Melo Guilherme Dias et al., “Anti-Covid-19 efficacy of ivermectin in the golden hamster” in bioRxiv, 22 November 2020 (submitted by applicant in an IDS) in combination with ABBASSI et al. (WO 2019016234 A1) and further in view of in view of Mengmeng Lu et al., “Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation” in Drug Delivery 2017 24(1): 622-631.
Claim 4 prophylactically treats COVID-19 in a subject at high risk for exposure to SARS-CoV-virus or who has recently been exposed to SARS-CoV-2, the subject test negative for the virus; the method comprises subcutaneously administering to the subject, with a frequency of no more than once every 21 days. It is the dose administered by the artisan to the subject that treats COVID-19.
de Melo Guilherme Dias subcutaneously injected hamster animals with 400 mg/kg of ivermectin after inoculating the hamster animals with SARS-CoV-2 (page 3, lines 5-32). Inoculating the hamsters with SARS-CoV-2 meets the limitation of “recently exposed” and “high risk for exposure” and these hamsters were negative for COVID at the time they were infected and at least at day 1 of the infection. Because it is the administered ivermectin that inhibits development, the ivermectin subcutaneously administered in de Melo Guilherme Dias also inhibits development of COVID-19. de Melo Guilherme Dias specifically states that ivermectin reduced clinical and/or prevented occurrence of anosmia, which is a typical symptom of COVID-19 (page 3, lines 30-32). de Melo Guilherme Dias subcutaneously injects ivermectin (page 3, line 11) and a single subcutaneous injection of 200 mL of freshly-diluted ivermectin as given (page 10, lines 24-28); which is 0.2 mL and is less than 1.5 mL. de Melo Guilherme Dias teaches ivermectin dose of 400 mg/kg or 100-200 mg/kg (page 10, lines 24-27).
ABBASSI teaches injectable sustained release composition comprising biodegradable triblock copolymer Av-Bw-Ax, where A is polyester, B is polyethylene glycol, v and x are number of repeat units ranging from 1 to 3000 and w is the number of repeat units ranging from 3 to 300 and v=x or vy-Az, where A is polyester and C is an end-capped polyethylene glycol with y and z being number of repeat units with y ranging from 2 to 250 and z ranges from 1 to 3000; and at least one active ingredient (see the whole document with emphasis on page 3, lines 11-35) and where the active agent is ivermectin (page 7, lines 2-3; page 7, lines 25; page 28, line 9; Table 5; Table 10 and claim 15). In one embodiment A is PLA (page 4, line 29; Table 5). The ranges from 2 to 250 or 3-300 for w and y contain within the range the claimed ranges of from 3-45; and 1 to 3000 for v and x and z contain the claimed ranges or 24-682; the number of repeat units ranging from 3 to 300 and v=x or vx. ABBASSI teaches triblock copolymer to diblock copolymer ratio of 1:5, 1:10, 1:19, 4:1, 3:1 and 2:1 (page 26, lines 2-5).
de Melo Guilherme Dias does not teach using biodegradable polymer with the ivermectin composition. Before the effective date of the invention, one having ordinary skill in the art, the artisan looking to de Melo Guilherme Dias and ABBASSI would be motivated to use biodegradable deblock and triblock copolymers of PLA-PEG/PLA-PEG-PLA for effective release of the active agent ivermectin.
Therefore, de Melo Guilherme Dias in combination with ABBASSI renders claim 4 prima facie obvious. For the frequency of dosing, ABBASSI teaches delivering active agent for at least 30 days or at least 90 days (page 8, lines 28-31, page 29, lines 23-30) and Mengmeng teaches that sustained release formulations have several advantages over conventional dosage forms; the sustained release formulations provide prolonged therapeutic effect and reduce frequency of dosing (see the title, last full paragraph, right column of page 622). Therefore, before the effective date of the invention, one having ordinary skill in the art, would be motivated to administer ivermectin in the form of sustained release with the expectation that the sustained release formulation would predictably provide prolonged therapeutic effect and reduce frequency of dosing, that includes dosing once every 30 days or 90 days including 21 days.
Thus, de Melo Guilherme Dias in combination with ABBASSI and in view of Mengmeng renders claim 4 prima facias obvious.
Claim(s) 7, 15-18, 20-21 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over de Melo Guilherme Dias et al., “Anti-Covid-19 efficacy of ivermectin in the golden hamster” in bioRxiv, 22 November 2020 (submitted by applicant in an IDS) in combination with ABBASSI et al. (WO 2019016234 A1) and further in view of in view of Mengmeng Lu et al., “Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation” in Drug Delivery 2017 24(1): 622-631.
Claims 7, 15-18, 20-21 and 26 depend on claim 4.
de Melo Guilherme Dias in combination with ABBASSI and in view of Mengmeng has been described above to render claim 4 prima facie obvious.
For claims 15-17, 20-21, the artisan seeking to deliver active agent to prolong therapeutic effect and reduce frequency of dosing would use sustained delivery form in order to predictably prolong the therapeutic effect and reduce frequency of dosing. Mengmeng teaches that sustained release formulations have several advantages over conventional dosage forms; the sustained release formulations provide prolonged therapeutic effect and reduce frequency of dosing (see the title, last full paragraph, right column of page 622). One having ordinary skill in the art recognizing that ABBASSI teaches delivering the active agent in at least 30 days or at least 90 days. Therefore, before the effective date of the invention, one having ordinary skill in the art, would be motivated to administer ivermectin in the form of sustained release with the expectation that the sustained release formulation would predictably provide prolonged therapeutic effect and reduce frequency of dosing, that includes dosing once every 30 days or 90 days including 21 days. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
For claim 18, de Melo Guilherme Dias teaches that ivermectin can be administered alone or in combination with other molecules (page 2, lines 31-32; page 3, line 5; page 5, lines 13-14). ABBASSI teaches administering biodegradable drug delivery composition comprising mixture of triblock copolymer and diblock copolymer (see the whole document with emphasis on the abstract), and active agent that is ivermectin (page 6, line 34; page 7, lines 2-3). Therefore, it would be reasonable to expect that the ivermectin can be administered alone before the administration of ivermectin in mixture of triblock copolymer and diblock copolymer matrix.
For claim 26, claim 4 has been described above to be rendered prima facias obvious over de Melo Guilherme Dias in combination with ABBASSI and in view of Mengmeng. Therefore for claim 26, the formulation subcutaneously injected would also be capable of being excisable.
Thus, de Melo Guilherme Dias in combination with ABBASSI and in view of Mengmeng renders claims 7, 15-18, 20-21 and 26 prima facias obvious.
No claim is allowed.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Conclusion
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/BLESSING M FUBARA/Primary Examiner, Art Unit 1613