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 .
Claim Objections
Claim 13 is objected to because of the following informalities: on the 3rd line from the bottom, applicant need to delete “or” (located in front of “a bicarbonate-based buffer,”). On the 2nd line from the bottom, applicant need to change “and” to --- or ---. Appropriate correction is required.
Claims 32 and 26 are objected to because of the following informalities: on the 2nd line of claim 32, applicant need to change “or said” to --- and said --- (this way, claim 32 would be saying that if said basic buffer is a borate-based buffer, it is sodium borate; if said basic buffer is a tetraborate-based buffer, it is sodium tetraborate or disodium tetraborate; and if said basic buffer is a bicarbonate-based buffer, it is sodium bicarbonate buffer, potassium bicarbonate buffer, ammonium bicarbonate buffer, triethylammonium bicarbonate buffer or carbonate bicarbonate buffer). Similarly, on the last line of claim 26, applicant need to change “or” to --- and --- (located in front of “(vii) said immunosuppressive drug”). Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-16, 18, 19, 21-23, 25-28 and 32-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a mixture of oligomers obtained by exposing (i) an indolium-based monomer of formula I, wherein R1-R3 independently is (C1-C6)alkyl; R4 is (C1-C12)alkyl substituted with one or more groups selected from -SO3-, -COO-, -PO3-2, -OH, -NH2, -N+(R’)3, phosphocholine and acetoxyethyl phosphocholine; R5-R8 being selected from H or C1-C6 alkyl, or R5 and R6 being H atoms or C1-C6 alkyl and R7 and R8 together (with the carbon atoms to which they are attached) form (C6-C14)aryl (optionally together with an additional monomer selected from dopamine, L-dopa, norepinephrine, serotonin and a mixture thereof) to (ii) suitable basic buffers as listed in [0044] of present specification, does not reasonably provide enablement for a mixture of oligomers obtained by exposing (i) any indolium-based monomer compound of formula I as described in claim 1 (including the embodiments: where the C1-C6 alkyl in the R1-R3 groups being optionally interrupted with heteroatom(s) selected from O, N and S; the C1-C12 alkyl in the R4 group being optionally interrupted with heteroatom(s) selected from O, N and S; R5-R8 being anything other than what is described above (i.e., R5-R8 being selected from H or C1-C6 alkyl, or R5 and R6 being H atoms or C1-C6 alkyl and R7 and R8 together (with the carbon atoms to which they are attached) form (C6-C14)aryl)) to (ii) any basic buffers. Furthermore, the specification, while enabling for certain oligomers stabilizing hydrophobic drugs comprising a 2-(N-anilino)pyrimidine group coupled to pi-conjugated system directly or via a nitrogen atom or AIEgenic drugs, does not reasonably provide enablement for any hydrophobic substance or any hydrophobic drug. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Citing In re Wands, 858 F.2d 731, 737 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), MPEP 2164.01(a) sets out the following factors to consider when determining whether a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The nature of the invention: instant invention is drawn to a composition comprising a mixture of oligomers obtained by exposing an indolium based monomer (optionally together with an additional monomer selected from dopamine, L-dopa, norepinephyrine, serotonin and a mixture thereof) to a basic buffer, where the oligomers stabilize a hydrophobic substance (such as a hydrophobic drug).
The breadth of the claims: in claim 1, applicant claims a composition comprising a mixture of oligomers obtained by exposing any indolium based monomer that fits instant formula I (optionally together with an additional monomer selected from dopamine, L-dopa, norepinephyrine, serotonin and a mixture thereof) to any basic buffer, and in claim 21, the composition further comprises any hydrophobic substance (i.e., any nonpolar materials that repel water instead of mixing or dissolving in it), examples of which can include plastics, waxes, oils and fats, etc. (where the oligomers stabilize such hydrophobic substance).
The state of the prior art: There seems to be no prior art on the mixture of oligomers produced by exposing an indolium-based monomer of instant formula I (with or without instant additional monomer(s)) to a basic buffer.
The level of one of ordinary skill: A chemist or a pharmaceutical scientist with an advanced degree (or equivalent) with at least 2-5 years of formulating pharmacological compositions.
The level of predictability in the art: As discussed above, there seems to be no prior art on the mixture of oligomers produced by exposing an indolium-based monomer of instant formula I (with or without instant additional monomer(s)) to a basic buffer. Thus, the level of predictability is low. In [00122], applicant themselves state the following:
[00122] This analysis identified two potent dye products with absorbance peaks in 555nm and 595nm which we named R555 and R595 (Fig. 2C, right panel). To our surprise, the reaction mixtures for these dye products contained only indoliums reagents in bicarbonate buffer without aldehydes which are required for this type of dye synthesis. Despite searching the scientific literature and the SciFinder database, no publication reporting monomeric indolium reactions in weak basic buffers was found. In our experiment, we found that all three indoliums reacted in weak basic buffers, but only the sulfated one acted as nanoparticle drug stabilizers.
The amount of direction provided by the inventor: Applicant provide in present specification directions or guidelines on how to make and use of oligomers obtained from several specific monomer compounds of formula I (1,1,2-trimethyl-3-(4-sulfobutyl)benz[e] indolium inner salt (In820), 2,3,3-trimethyl-1-(4-sulfobutyl)indolium inner salt (In783), (5-carboxypentyl)-1,1,2-trimethyl-1Hbenz[e]indolium bromide (IN-CO2) and 1-(2-hydroxyethyl)-2,3,3-trimethyl-3H-indolium iodide (In-OH)) and a bicarbonate buffer (sodium bicarbonate) (even then, Applicant observed that only R595 dye (produced from In820) was an ultra-stabilizer for both nilotinib and trametinib (specific AIEgenic drugs)). However, those exemplified monomers (In820, In783, In-CO2 and In-OH) are not highly representative of the monomers of the claimed formula I and sodium bicarbonate buffer certainly does not represent the entire class of basic buffers. Also, those AIEgenic drugs definitely do not represent the class of all hydrophobic substances (or even all hydrophobic drugs).
The quantity of experimentation needed to make or use the invention: Since little is known in the prior art about the mixture of oligomers produced by exposing an indolium-based monomer of instant formula I (with or without instant additional monomer(s)) to a basic buffer, and the art is unpredictable as to their ability to stabilize a hydrophobic substance (or a hydrophobic drug), present specification would need more detail as to how to make and use the invention so that the scope of the claims is commensurate with the scope of the enabling disclosure.
In conclusion, analysis of the preceding Wands factors supports the conclusion that the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims, and thus one of ordinary skill in the art would not be able to make and use the claimed invention as a whole without exercising undue experimentation.
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure: Narayanan et al (“A New Method for the Synthesis of Heptamethine Cyanine Dyes: Synthesis of New Near-Infrared Fluorescent Labels”, J. Org. Chem. 1995, 60, pg.2391-2395) teaches (see under “Results and Discussion” on pg.2391-2392) the following compounds (Narayanan’s “Quaternary Salts 1”):
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The compound 1a (with Y being H atom, Z being CMe2 and R1 being (CH2)4SO3) teaches instant indolium-based monomer of formula I (instant R4 being C4alkyl substituted with -SO3-). However, such compound is not exposed to a basic buffer as required in instant claim 1. Instead, it is mixed with 2-chloro-1-formyl-3-(hydroxymethylene)cyclohex-1-ene (Narayanan’s “Bisaldehyde 2”) and heated, and the mixture is refluxed in a mixture of solvents (1-butanol and benzene) without using any catalyst. The water formed during the reaction is removed as an azeotrope, and the resulting product (heptamethine cyanine dyes) is filtered and then washed with diethyl ether. Narayanan’s Bisaldehyde 2 (2-chloro-1-formyl-3-(hydroxymethylene)cyclohex-1-ene is not a basic buffer, and thus Narayanan does not teach or suggest instant composition of claim 1 comprising a mixture of oligomers obtained by exposing an indolium-based monomer of formula I (optionally together with the listed additional monomer) to a basic buffer.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
August 8, 2026
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