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
The instant application claims benefit to domestic provisional application Nos. 63/405,163 filed on September 9, 2022 and 63/402,321 filed on August 30, 2022.
Status of Claims
Acknowledgement is made of original (1-19) claims filed on August 30, 2023. Claims #1-19 are pending in instant application.
Information Disclosure Statement
No IDS statement has been filed.
Claim Interpretation
Regarding claim 18, Applicant defines “pharmaceutically-acceptable” as:
“not biologically or otherwise undesirable, in that it can be administered to a subject without excessive toxicity, irritation, or allergic response, and does not cause any undesirable biological effects or interact in a deleterious manner with any of the other components of the composition in which it is contained.” (see instant spec. at p. 24 lines 10-13)
Applicant defines “carrier” as:
“one or more compatible base compositions” with which the active ingredient (e.g., above-described compounds) is combined to facilitate the administration of ingredient, and which is suitable for administration to a patient. Such preparations may also routinely contain salts, buffering agents, preservatives, and optionally other therapeutic ingredients or adjuvants.” (see instant spec. at p. 24 lines 14-18).
A pharmaceutically acceptable carrier is thus understood to be any art-recognized pharmaceutically acceptable carrier.
In addition, the phrase “to inhibit or treat infections, cancer, brain conditions, and/or inflammatory conditions” is understood to recite an intended use that is fully satisfied by the structural limitations set forth in the body of the claim (i.e. an adduct or dimer according to claim 17 and a carrier) (see MPEP § 211.02(II); 2111.04(I)).
Regarding claim 19, Applicant does not define “subject” in the specification. Accordingly, a subject is understood to encompass animals or cells.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The title should reflect the structure of the disclosed compounds. The following title is suggested: METHOD OF MAKING HARMINE DERIVATIVE ADDUCTS AND DIMERS.
Claim Objections
Claim 7 is objected to because of the following informalities:
Claim 7 line 2 states “(C2H3ClO) propionyl chloride (C3H5ClO), 3-Chloropropionyl chloride (C3H4Cl2O), …” but is missing a comma and should read “(C2H3ClO), propionyl chloride (C3H5ClO), 3-Chloropropionyl chloride (C3H4Cl2O), …”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 5, 11-12 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 5, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 11-12, the claims list single atoms as potential substituents connected to the general structures by one bond (e.g. R’s may be “Oxygen”, “Sulfur”, “metals”). This raises issues of valency, one skilled in the art would not recognize as possibilities as written.
Further regarding claim 11, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Further regarding claims 11-12, the phrase “selected from the group of possible options” and in the table headings the phrase “Possible substituents”, renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Are the substituents limited to those listed or are they exemplary? See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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.
Claims 17, 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jiang et. al.1
Per MPEP § 2113, "[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." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Regarding claim 17, Jiang teaches compounds 1a-c, 2a-c, 3a-c, 4a-c, and 8, which are β-carboline dimers or adducts (see Jiang at p. 372 Scheme 1).
Jiang Harmine and Harmaline Dimers
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Jiang Harmaline Adduct
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Regarding claim 19, Jiang teaches administering β-carboline dimers to murine leukemia cells (reading on a subject with cancer) (see Jiang at p. 372 right col. “Biology”).
Claims 17-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by U.S. Patent No. 10,947,253 to Blagg et. al.2 Although the claims at issue are not identical, they are not patentably distinct from each other.
Per MPEP § 2113, "[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." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Regarding claim 17, Blagg teaches β-carboline dimer compounds (see Blagg claims 1-8).
US’253 Claim 1
Instant Dimer Formula (b)
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Regarding claim 18, Blagg teaches a composition comprising a β-carboline dimer compound and a carrier (see Blagg claim 9).
Regarding claim 19, Blagg teaches a method of treating a human subject with cancer comprising administering a β-carboline dimer compound (see Blagg claim 10).
Claim Rejections - 35 USC § 103
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.
Claims 1-12, 14-17, 19 are rejected under 35 U.S.C. 103 as being unpatentable over Jiang et. al.3 in view of Yu et. al.4 and Hayashi et. al.5
Regarding claims 1-6, 8-9, 12, 17 and dimers, Jiang teaches a synthesis of harmaline and harmine dimers (instant claims 9, 12) from tryptamine (instant claims 2-4) with a diacid chloride (n = 4 adipoyl chloride, n = 6 octanedioyl chloride, or n = 10 dodecanedioyl chloride) (instant claims 5-6) and triethylamine, condensing with phosphoryl chloride (instant claim 8) (see Jiang at p. 372 Scheme 1).
Regarding claim 10, Jiang teaches oxidizing the harmaline dimers to harmine dimers with Pd/C, p-cymene, at reflux (see Jiang at p. 372 Scheme 1).
Further regarding claim 12, Jiang’s 3a-c dimers read on instant Formulas a and b when R1-R3 are H.
Regarding claim 15, Jiang teaches yields for harmaline dimers 3a as 81%, 3b as 92%, 4a as 73%, and 4b as 73.3% (see Jiang at p. 371 and at p. 372 Scheme 1).
Regarding claims 1, 11, 17 and adducts, Jiang teaches a synthesis of harmine adducts (instant claims 1), from tryptamine (instant claims 2-4) with a monoacid chloride (n = 4, 6, or 10), condensing with phosphoryl chloride (instant claim 8) (see Jiang at p. 372 Scheme 1).
Regarding claim 19 and a method of treating, Jiang teaches administering graded concentrations of harmine and harmaline dimers to murine leukemia cells, reading on treating cancer in a subject (see Jiang at p. 372 right col. “Biology” and at p. 373 Table I).
The prior art differs from the instant claims as follows:
Claim 1 states acetonitrile (MeCN) as the reaction solvent and Jiang teaches dichloromethane (DCM) as the reaction solvent
Claims 1, 14, 16 are drawn to a one-pot synthesis strategy which is not specified by Jiang
Claim 7 lists monoacid chlorides differ from Jiang’s monoacid chlorides
However,
Regarding (i), Yu teaches a method of making a dimer from a primary amine with a diacid chloride and triethylamine in acetonitrile (see Yu at p. 2 Scheme 1 and at p. 2 right col. “Synthesis of C4”).
Instant
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Prior Art Jiang
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Prior Art Yu
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Regarding (ii), Hayashi teaches one-pot syntheses of reactions in the same reaction vessel is an efficient strategy (see Hayashi at Abstract).
Regarding (iii), Jiang still teaches forming adducts or dimers, with mono or diacid chlorides.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Regarding (i), per MPEP § 2143(I)(B), a prima facie case of obviousness exists for simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute Yu’s acetonitrile solvent system for Jiang’s DCM solvent system because Yu teaches acetonitrile is a suitable solvent for a dimerization with an acid chloride, the same purpose of Jiang’s synthesis.
Regarding (ii), per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to one skilled in the art to improve upon the synthesis taught by Jiang and Yu by making it a one pot reaction because Hayashi teaches a one-pot strategy is more efficient.
Regarding (iii), it would have been obvious to one skilled in the art to use a monoacid chloride variant of Jiang’s diacid chlorides (e.g. instant octonoyl chloride vs Jiang’s octanedioyl chloride), because Jiang teaches using monoacid dichlorides to form adducts and diacid chlorides for forming dimers. Accordingly, one skilled in the art would recognize any monoacid chloride would be suitable for forming a harmine or harmaline adduct, because it contains one reactive C(O)Cl moiety, such as those taught by Jiang (see MPEP § 2144.07).
Bi-Functional Diacid Chloride
Monoacid Chloride
Jiang
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Furthermore, it is well-within the ordinary skill in art to incorporate one suitable reaction solvent in lieu of another. Furthermore, it is well-within the ordinary skill in art to modify a known synthesis with a known synthetic strategy in order to improve the synthesis. Furthermore, it is well-within the ordinary skill in art to select a monoacid chloride for use in forming a harmine or harmaline adduct for the same purpose as taught by the prior art.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Jiang in view of Yu and Hayashi as applied to claims 1-12, 15, 17, 19 above and in further view of Dunetz et. al.6
The prior art differs from the instant claims as follows: while Jiang and Yu teach a method of making an adduct or dimer of claim 1, they do not specify anhydrous solvent.
However,
Dunetz teaches activation of a carboxylic acid as the corresponding acid chloride and subsequent reaction with an amine is one of the oldest approaches to amide bond formation (see Dunetz at p. 141 right col. “2.1 Coupling via Acid Chloride”). Dunetz teaches acid chlorides are water sensitive, and acid chloride/amine reactions can be performed under anhydrous conditions using an organic base such as triethylamine (see Dunetz at p. 142 left col. ¶3).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to one skilled in the art to modify the synthesis of an adduct or dimer as taught by Jiang and Yu by using anhydrous acetonitrile because Dunetz warns artisans acid chlorides are sensitive to water.
Furthermore, it is well-within the ordinary skill in art to select an anhydrous solvent for use in a known synthesis for the same purpose as taught by the prior art.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Claim 18 rejected under 35 U.S.C. 103 as being unpatentable over Jiang in view of Yu and Hayashi as applied to claims 1-12, 15, 17, 19 above and in further view of Remington et. al.7
The prior art differs from the instant claims as follows: while Jiang and Yu teach a method of making an adduct or dimer of claim 1, they do not specify formulation with a carrier.
However,
Regarding claim 18 and a composition, Remington teaches formulating drugs with carriers for drug delivery for improving stability or to enhance therapeutic efficacy (see, e.g. Remington at p. 953 right col. “colloidal drug carriers”).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to arrive at the instantly claimed invention with a reasonable expectation of success in view of the prior art for at least the following reason(s):
Per MPEP § 2143(I)(D), a prima facie case of obviousness exists for applying a known technique to a known method or product ready for improvement to yield predictable results. It would have been obvious to one skilled in the art to improve upon the anti-cancerous dimers taught by Jiang by formulating in a composition for administering to a subject because Remington teaches combining drugs with carrier improves stability and efficacy.
Furthermore, it is well-within the ordinary skill in art to combine a therapeutically active drug with a known carrier to form a composition for the same purpose as taught by the prior art.
Therefore, an artisan would arrive at the same invention as presently claimed for reasons taught in the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,947,2538. Although the claims at issue are not identical, they are not patentably distinct from each other.
Per MPEP § 2113, "[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." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Regarding claim 17, US’253 claims β-carboline dimer compounds (see US’253 claims 1-8).
US’253 Claim 1
Instant Dimer Formula (b)
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Regarding claim 18, US’253 claims a composition comprising a β-carboline dimer compound and a carrier (see US’253 claim 9).
Regarding claim 19, US’253 claims a method of treating a human subject with cancer comprising administering a β-carboline dimer compound (see US’253 claim 10).
Accordingly, the claims are not patentably distinct.
Claims 17, 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,576,9029. Although the claims at issue are not identical, they are not patentably distinct from each other.
Per MPEP § 2113, "[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." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
US’902 teaches methods of administering a β-carboline dimer (reading on a product of instant claim 17) to treat COVID-19 (reading on instant claim 19 treating an infection).
US’902
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Accordingly, the claims are not patentably distinct.
Claims 17-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12,129,265 B210. Although the claims at issue are not identical, they are not patentably distinct from each other.
Per MPEP § 2113, "[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." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Regarding claims 17-18, US’265 claims compositions comprising β-carboline moiety dimers (see US’265 claim 1) and carriers (see US’265 claim 2).
US’265
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Accordingly, the claims are not patentably distinct.
Claims 17-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 13-19 of copending Application No. 18/327,21311 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Per MPEP § 2113, "[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." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Regarding instant claim 17, App’213 claims compounds with β-carboline moieties (see App’213 claims 1-10).
App’213 Claim 1
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Regarding instant claim 18, App’213 claims a composition comprising a disclosed β-carboline compound and a carrier (see App’213 claim 19).
Regarding instant claim 19, App’213 claims a method of treating a microbial infection (see App’213 claim 13-18).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-19 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SOPHIA J REILLY whose telephone number is (703)756-5669. The examiner can normally be reached 9:00 am - 5:00 pm EST M-F.
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/S.R./Examiner, Art Unit 1627
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
1 Jiang et. al. "Cytotoxic Bis-3,4-dihydro-b-carbolines and Bis-b-carbolines" Journal of Enzyme Inhibition and Medicinal Chemistry, 2002, 17, 6, 369–374. DOI: 10.1080/147563021000005631. Hereinafter Jiang.
2 Filed August 5, 2019 and patented March 16, 2021. Hereinafter Blagg or US’253 (see below Double Patenting Rejections).
3 Jiang et. al. "Cytotoxic Bis-3,4-dihydro-b-carbolines and Bis-b-carbolines" Journal of Enzyme Inhibition and Medicinal Chemistry, 2002, 17, 6, 369–374. DOI: 10.1080/147563021000005631. Hereinafter Jiang.
4 Yu et. al. "Unusual role of labile phenolics in imparting flame resistance to polyamide" Polymer Degradation and Stability, 2020, 175, 109103. DOI: 10.1016/j.polymdegradstab.2020.109103. Hereinafter Yu.
5 Hayashi et. al. "Pot economy and one-pot synthesis" Chem. Sci. 2016, 7, 866. DOI: 0.1039/c5sc02913a Hereinafter Hayashi.
6 Dunetz et. al. "Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals" Org. Process Res. Dev. 2016, 20, 140-177. DOI: 10.1021/op500305s. Hereinafter Dunetz.
7 Remington's Pharmaceutical Sciences (21st Ed) New York, NY: Lippincott Williams and Wilkins 2005. Select pages. Hereinafter Remington.
8 Filed August 5, 2019 and patented March 16, 2021. Hereinafter US’253.
9 Filed December 1, 2020 and patented February 14, 2023. Hereinafter US’902.
10 Filed December 1, 2020. Patented October 29, 2024. Hereinafter US’265.
11 Filed June 1, 2023. Hereinafter App’213.