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 .
Status of the Claims
Applicant’s election without traverse made in the response filed on January 2nd, 2026 is the compound, 3-(l,3-bis (7-methoxy-4,9-dihydro-3H-pyrido [3,4-b ]indol-1-yl )propan-2-yl )- lH-indol e-5-carbonitrile, also referred to as ”GK580” (represented by the structure):
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Claims 1-2, 5, and 7-20 read on the elected species, with claim 10 being specific to the elected species, and claims 1-2, 5, 7-9, and 11-20 being generic to the elected species (where R1 is a substituted fused heterocyclic ring, each R2 is hydrogen, and R3 is an alkoxy or a hydrogen). Claims 3-4 and 6 are withdrawn.
Claims 1-2, 5, 7-9, and 11-20 are pending and examined on their merits.
Claim Objections
Claim 2 includes a wide variety of variables for R1 that do not read on the elected species, including non-heterocyclic ring structures.
Priority
The present application claims the priority benefit of U.S. Provisional Patent Application
No. 63/405,163, filed September 9, 2022 and U.S. Provisional Patent Application No.
63/347,752, filed June 1, 2022.
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 7, 9 and 10 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.
Claims 7, 9 and 10 are directed to compounds that depend from β-carboline moieties including the referenced compounds below (identified in claim 1).
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The compound in claim 9 depends from claim 7 and the compound in claim 10 depends from claim 1 that identify the variables for the compounds of the instant claims to be selected from a group of:
R1 is independently selected from the group consisting of substituted or unsubstituted
aromatic, antiaromatic, or non-aromatic compounds up to 10 atoms, and substituted
or unsubstituted fused heterocyclic rings.
R2 is independently selected from the group consisting of hydrogen, halogens,
sulfonyl chloride, sulphonic acid, sulfonamide, thiol, hydroxy, alkoxy, poly
methoxy, H-donor groups, H-bond acceptor groups, aromatic, antiaromatic, or nonaromatic
compounds up to 10 atoms, and substituted or unsubstituted fused heterocyclic rings.
R3 is independently selected from the group consisting of hydrogen, oxygen,
halogens, sulfonyl chloride, sulphonic acid, thiols, alkyls, nitro groups, hydroxy,
alkoxy, H-donor groups, H-bond acceptor groups, aromatic, antiaromatic, or nonaromatic
compounds up to 10 atoms, and substituted or unsubstituted fused heterocyclic rings.
Claim 9 is drawn to a genus of the compound (the R1-3 groups are as shown above):
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Claim 10 is drawn to species of the compounds in claim 1, (the R1-3 groups are as shown above) including:
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The compounds of the instant claims do not fit within the limitations of claim 1 where the -OH is removed without any support or explanation in the claims. One of ordinary skill in the art cannot reasonably determine the metes and bounds of removal of the hydroxyl group in the β-carboline moieties that result in the compounds of the instant claims. As described in the MPEP 2111.01, “Though understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment.” Superguide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875, 69 USPQ2d 1865, 1868 (Fed. Cir. 2004). See also Liebel-Flarsheim Co. v. Medrad Inc., 358 F.3d 898, 906, 69 USPQ2d 1801, 1807 (Fed. Cir. 2004).
Claim Rejections - 35 USC § 102 (a)(1)
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.
(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 1, 2, 5, and 7-12 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, filed August 5, 2019 and patented March 16, 2021. Hereinafter Blagg or ’253. Although the claims at issue are not identical, they are not patently distinct from each other.
By way of background, Beta-carboline is an indole alkaloid which has been identified as a valuable heterocyclic nucleus in the field of medicinal chemistry. It has different biological activities like antibacterial, anticancer, antifungal, antimalarial, antileishmanial, anti-HIV, anti-trypanosomal, and anti-toxoplosmal respectively in various medicinal compounds. The study of various potent beta-carboline derivatives and their synthetic aspects helps to design other potent derivatives for the effective treatment of multiple diseases like leishmaniasis, malaria, cancer, AIDS, tuberculosis, and bacterial and fungal infections. Incorporation of beta-carboline nucleus improves physiochemical and pharmacological properties. See Thatikayala, et. al.1
Blagg details in the Abstract of the invention, novel fused tricyclic or bicyclic dimers, such as β-carboline and quinoline moieties with a central linker, exhibit anticancer activities against a variety of human cancer cell lines. The dimer compounds can be used in anti-cancer therapeutic compositions useful in the treatment of human cancers. Further, in the Field of the Invention, more particularly, the invention provides
dimers having two fused tricyclic (e.g., β-carbolines such as harmaline) or two fused bicyclic (e.g., quinoline and isoquinoline) moieties with a central linker.
Bragg details in column 6, a general reaction scheme for the tricyclic harmaline/phenyl aldehyde dimers of the invention were prepared via a condensation reaction between two β-carboline molecules (harmaline) and a phenyl aldehyde. As shown below:
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Regarding claim 1, applicant perports to have invented β-carboline molecules based on the Harmaline compound used in the synthesis of a of a tricyclic dimer for example:
US’253 β-carboline molecules (harmaline)
Instant Claim 1 (top left β-carboline molecule)
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R2 and R3 are both independently selected from the group consisting of hydrogen
Therefore, Blagg anticipates the use of β-carboline molecules used in the synthesis of dimer compounds.
Regarding claim 5, applicant further limits the compound of claim 1 wherein the β-carboline moiety is harmaline, harmine, or tetrahydro harmine.
As stated above, Blagg anticipates the use of β-carboline that is based on the harmaline compound.
Regarding claim 7, applicant identifies a second β-carboline moiety used for the creation of the dimer molecule.
As shown in the general reaction scheme for the tricyclic harmaline/phenyl aldehyde dimers were prepared via a condensation reaction between two β-carboline molecules (harmaline) and a phenyl aldehyde.
Blagg anticipates using two β-carboline molecules to create the dimer in a two-step synthesis.
Regarding claim 8, that further limits claim 7, applicant identifies the second β-carboline moiety is a harmaline, harmine, or tetrahydro harmine.
As stated above in the rejection to claims 5 and 7, Blagg anticipates the use of 2 β-carboline molecules; both of which are harmaline compounds utilized to make a dimer.
Regarding claim 9, that further limits claim 7 and identifies a series of dimers a, b and c, for example see dimers a and b below. Blagg teaches β-carboline dimer compounds (see Blagg claims 1-8).
US’253 Claim 1
Instant Dimer Formula (a)
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Blagg anticipates the dimer formulas of the compounds of the instant claim including a composition comprising a β-carboline dimer compound and a carrier (see Blagg claim 9).
Regarding claim 10, that further limits claim 1, wherein the compound is a polycyclic compound comprising at least one of said fused tricyclic compounds and having the structure: (only 2 of 4 compounds listed for reference).
US’253 General reaction scheme the tricyclic harmaline/phenyl (product)
Instant Dimer Formula (a)
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Although the claims are not identical, they are not patently distinct from each other. Bragg in ‘253 anticipates the attachment of a phenyl ring instead of the applicants additions. The core of the compound is fundamentally the same.
Regarding claim 11, applicant purports to have invented a used tricyclic compound synthesis process comprising reacting a first amount of harmaline with a compound comprising an aldehyde moiety and a solvent to yield a product comprising a tricyclic β-carboline adduct compound that requires the reaction to take place in an extraction glassware set up comprising an extractor body having a top opening and a bottom opening, a condenser having a bottom opening configured to receive said top opening of the extractor body, and a flask having a top opening, said top opening of the extractor body being attached to said bottom opening of the condenser and said bottom opening of the extractor body being attached to said top opening of the flask.
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Blagg teaches in the general reaction scheme for the tricyclic harmaline/phenyl aldehyde dimers of the invention were prepared via a condensation reaction between two β-carboline molecules (harmaline) and a phenyl aldehyde that includes the adduct (circled above). Further, Blagg details that while other solvents were explored, methanol was found to provide the best yields for this reaction (col. 6). Therefore, Blagg anticipates the method of producing the dimer and the intermediate that results from the addition of a harmaline to an aldehyde in the presence of the solvent methanol.
The apparatus identified by the applicant is moot.
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 12, that further limits claim 11, wherein said reacting further comprises reacting a second amount of harmaline with a compound comprising an aldehyde moiety, the solvent, and the product comprising a tricyclic β-carboline adduct compound to yield a product comprising tricyclic β-carboline dimer compound comprising two β-carboline moieties linked via a CH2 methine group bonded to respective methyl substituents of the β-carboline moieties.
As stated in the rejection to claim 7 above, Blagg anticipates using two β-carboline molecules to create the dimer in a two-step synthesis.
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.
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.
Claims 2, and 13-20 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 10,947,253 to Blagg et. al, filed August 5, 2019 and patented March 16, 2021. Hereinafter Blagg or ’253 as applied to claims 1, 2, 5, and 7-12 above and in view of Dai, et. al., β-Carboline alkaloid monomers and dimers: Occurrence, structural diversity, and biological activities, European Journal of Medicinal Chemistry, 157 (2018) pages 622-656 (hereinafter Dai).
Blagg details in the Abstract of the invention, novel fused tricyclic or bicyclic dimers, such as β-carboline and quinoline moieties with a central linker, exhibit anticancer activities against a variety of human cancer cell lines. Bragg details in column 6, a general reaction scheme for the tricyclic harmaline/phenyl aldehyde dimers of the invention were prepared via a condensation reaction between two β-carboline molecules (harmaline) and a phenyl aldehyde. He does not teach the use of a β-carboline molecules derived from harmaline has activity against microbial activity against bacteria, fungus or viruses. Dai reviews the biological activity of β-Carboline alkaloids that belong to a family of natural and synthetic products with great structural diversity and outstanding biological activities. He evaluates the effectiveness of both monomers and dimers in the evaluation.
Claims 13-20 of the instant application are drawn to methods of inhibiting microbial activity (as in claim 13), administering said compound or a composition comprising said compound to a subject in need thereof (as in claim 14), wherein said microbe is a bacteria, fungus, or virus (as in claim 15), a method for treatment or prophylaxis of a microbial infection, (as in claim 16), wherein said subject is suffering from amicrobial infection before said administering step (as in claim 17), wherein said subject is at risk of a microbial infection before said administering step (as in claim 18), an antimicrobial composition comprising a fused tricyclic compound according to claim 1 dispersed in a pharmaceutically-acceptable carrier (as in claim 19) and a medicament for inhibiting microbial activity and/or treating a microbial infection, said medicament comprising a fused tricyclic compound according dispersed in a pharmaceutically-acceptable carrier (as in claim 20).
The use of dimers to treat a variety of diseases or conditions has been described in detail by Dai including the interest in the effect of dimers of β-carboline due to the compounds substantial activity compared to the monomers. For example:
“Interestingly, recent original reports have highlighted the trend that β -carboline dimers display a substantially higher bioactivity than the corresponding monomers in a variety of contexts [30]. Thus, we have selected b-carbolinemonomers and dimers as a highlight topic for this focus review.”
Dai, page 623, col 1, paragraph 2 (emphasis added) and further,
“The occurrence and structural diversity of β -carbolines have
been detailed regarding both monomers and dimers in the first
section. The monomer part has been structured according to the (i) discovery date, and (ii) structural characteristics. The dimer part has been structured according to the most commonly reported position of the monomer linker. In the following section, the remarkable biological activities of both monomers and dimers have been highlighted: antitumor, antiparasitic, antimicrobial, antiviral, neuropharmacological, antioxidant, antidiabetes, and aphrodisiac properties.”
Dai, page 623, col 2 paragraph 1 (emphasis added).
Therefore, Blagg teaches the reaction scheme for the tricyclic harmaline/phenyl aldehyde dimers of the invention and the preparation of the dimers prepared via a condensation reaction between two β-carboline molecules (harmaline) and a phenyl aldehyde. Dai teaches the use of the β-carboline dimer molecules have increased bioactivity compared to the monomeric versions of the β-carboline molecules and the dimeric versions of the molecule have been shown to have both antimicrobial and antiviral potency. Given the teachings of Blagg in concert, with Dai it would have been prima facie obvious to one skilled in the art to combine the teachings Blagg and Dai of using the dimer of the β-carboline harmaline for use in the treatment of a microbe or a virus. Accordingly, the instant claims are rejected.
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 1-2, 5, 7-9, and 11-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,947,2532. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 9 the β-carboline dimer compounds are based on the harmaline molecule and are reacted to form a dimer compounds (see US’253 claims 1-8).
US’253 Claim 1
Instant Dimer Formula (a)
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Regarding claims 19 and 20, US’253 claims a composition comprising a β-carboline dimer compound and a carrier (see US’253 claim 9).
Accordingly, the claims are not patently distinct.
Claims 1-2, 5, 7-9, and 11-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/458,604 (reference application); hereinafter ‘604. Although the claims at issue are not identical, they are not patentably distinct from each other.
Even though the compounds listed in 604 are drawn to a method of synthesis and the compounds of the instant claims are drawn to compounds; resulting from synthesis they are not 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 claims 1 and 5, Application’604 claims compounds with β-carboline moieties wherein the β-carboline carboline moiety is harmaline, harmine, or tetrahydro harmine. (See App’604 claim 11.
Adduct Formula (b) of 604 (Claim 11)
Instant Application Claim 1
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M is 0
R1 Fused heterocyclic rings
R2 H, halogens Fused heterocyclic rings,
R3 Hydrogen, Oxygen, halogens, sulfonyl chloride, Sulphonic acid, thiols, alkyls, hydroxy, H-donor groups, H-bond acceptor, Nitro groups, hydroxy,
Alkoxy
R1 Fused heterocyclic rings
R2 H, halogens, Fused heterocyclic rings
R3 Hydrogen, Oxygen, halogen sulfonyl chloride, Sulphonic acid, thiols, alkyls, hydroxy, H-donor groups, H-bond acceptor, Nitro groups, hydroxy,
Alkoxy
Regarding instant claim 1 the core compound of the application and the method of synthesizing the compound (b) of ‘604 is identical given the limitations for the variables as outlined above.
Regarding instant claim 5 the method claim of ‘604 utilizes the same said adduct in compound b); harmaline.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-2, 5, 7-9, and 11-20 are rejected.
No Claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL RANDALL GAUGER whose telephone number is (571)272-1325. The examiner can normally be reached M-F 7:30-5:00.
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/P.R.G./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Beta-carboline as a promising heterocyclic nucleus: Synthetic aspects, pharmacological potential and structure activity relationship, European Journal of Medicinal Chemistry Reports Volume 6, December 2022
2 Filed August 5, 2019 and patented March 16, 2021. Hereinafter US’253.