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
Claims 1-5 and 7-20 are pending. Acknowledgment is made of Applicant’s amendments filed May 11, 2026. Claim 6 had been canceled in a prior amendment.
Election/Restrictions
Applicant’s election without traverse of the following species in the reply filed on May 11, 2026 is acknowledged:
Compound of Formula I: MP 3269
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Compound of Formula II: MB-102
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Organic solvent (claims 1 and 5): ethanol and ethyl acetate
Catalyst (claims 1 and 7): Pd/C
First solvent (claim 16): DMSO
Anti-solvent (claim 16): ethyl acetate
First solvent (claim 18): DMSO
Anti-solvent (claim 18): ethyl acetate
The above election requirement has been partially expanded to include any organic solvent as the organic solvent of claims 1 and 5 and item iii.
Priority
This application claims priority to U.S. Provisional Application No. 63/385,098, filed November 28, 2022.
Claim Rejections – Improper Markush
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Claims 1, 4-5, and 7-20 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The Markush grouping of Claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The Markush grouping is directed to compounds of Formulas (I) and (II) depicted below:
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The variables PG, X1, and X2 encompass a myriad of substituents forming compounds so diverse that they will confer the above structure complete different structural and chemical properties. For example, X1 and X2 can be any natural or α-amino acid or polypeptide chain that includes one or more natural and unnatural α-amino acids, which encompasses countless combinations. Even just limiting to the 22 proteinogenic amino acids and a chain length of 3 amino acids, there would be over 10,000 possibilities for each position Y1 and Y2, let alone accounting for the variability encountered with longer chain lengths or incorporating the hundreds of unnatural α-amino acids. Alternatively, X1 and X2 may be -N(R1)(R2) wherein R1 can be one of over 20 extremely broad chain definitions. For example, when R1 is -(CH2)a(CH2CH2O)b (CH2)cNR10 CONR11(CH2)d(CH2CH2O)eR20, a, c, and d can be anywhere from 0 to 10, and b and e can be anywhere from 0 to 100. Thus, the compounds according to Formulas (I) and (II) include compounds with no common core structure that are not obvious variants of each other. With no significant structural similarity, the Markush grouping is improper.
Because claims 4-5 and 7-20 depend from claim 1 and do not narrow the scope of the Markush structure, they inherit the improper Markush grouping of claim 1.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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, 4 ,5, and 7-20 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 method of preparing a compound of Formula II wherein each of Y1 and Y2 is selected from hydrogen, amine, and amide; X1 and X2 are selected from a single amino acid; and the protecting group, solvents and catalysts are selected as claimed; does not reasonably provide enablement for the full scope of compounds of Formulas I and II. 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.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to a method of preparing a compound of Formula II comprising forming a mixture comprising a compound of Formula I, an organic solvent, a catalyst, and H2, and reacting the mixture. The scheme is depicted below:
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Breadth of the invention:
The scope of the claimed invention is very broad, as the compounds of Formulas I and II have a broad range of variability in groups X1, X2, Y1, and Y2 with a range of chemical activities, properties, and structures. For example, Y1 and Y2 can both be any ester, and X1 and X2 can each be any amino acid or any polypeptide chain, without limit on length. A chain consisting of three amino acids selected from only the 22 proteogenic amino acids has over 10,000 possibilities, each with its own reactive sites to consider.
State of the prior art and predictability in the art:
The invention is directed to a chemical reaction. It is well established that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The instant invention is directed in particular to catalytic hydrogenation to convert a compound of Formula I to a compound of Formula II. However, catalytic hydrogenation is not chemo-selective and will also react with other groups on the molecule. As Carey (Advanced Organic Chemistry Part B: Reaction and Synthesis, 2007, pp. 367-471) teaches, ketones, aldehydes, and esters can all be reduced to alcohols, and nitro compounds can be reduced to amines (p. 390, section 5.2). Thus, the reaction of catalytic hydrogenation may do more than simply deprotect the compound of Formula I and yield unwanted side reactions.
Level of ordinary skill in the art:
An ordinary artisan in the area of chemical synthesis would have experience in adjusting reaction conditions such as temperature, choice of solvent, and pressure to best optimize yield and minimize side reactions. The art of chemical synthesis, while complex, is routine in the art. However, given the extreme breadth of scope and variability encompassed by compounds of Formula I, the skilled artisan could not account for side reactions in the hydrogenation of any given compound of Formula I.
The amount of direction provided and working examples:
The compound core depicted with specific substituents represents a narrow subgenus for which applicant has provided sufficient guidance to make and use; however, the disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has only provided an example where X1 and X2 are serine and Y1 and Y2 are amine, and has not demonstrated that the reaction for the full scope of compounds of Formula (I) will go through as intended or predicted.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
MPEP § 2164.01 (a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for the claimed reaction of compounds of the full scope of Formulas I and II.
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.
The term “substantially free ofs” in claim 13 is a relative term which renders the claim indefinite. The term “substantially free” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what concentration of water would fail a solvent to be “substantially free of aqueous solvents”. For example, pure ethanol forms an azeotrope with water at 95% ethanol and 5% water.
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 1-5, 7-9, 12, and 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rajagopalan (J. Med. Chem. 2011, 54, 5048–5058).
Rajagopalan teaches the following reaction (p. 5050, Scheme 1, line 4).
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The reaction is performed in a mixture of ethanol and water, reacted with H2 and 10% Pd–C (p. 5050, Scheme 1, footnote a, definition of (f)). Specifically, the reaction was performed by adding compound 4d to a round-bottom flask containing ethanol, adding 10% Pd–C to the flask, then purging the reaction mixture with argon and stirring under H2 atmosphere for 5 hours at room temperature. The reaction mixture was filtered, washed with a 1:1 mixture of ethanol and water, and dried (p. 5054, right, para. 3, lines 1-4; preparation of 2c given on p. 5054, right, para. 1, lines 1-12). The reaction was done at atmospheric pressure (p. 5049, right, lines 5-9).
Compound 4d is the same compound as recited in instant claim 2 (the benzyl group Bn in instant claim 2 is identical to the phenyl group attached to a methylene group as depicted compound 4d). Compound 2d is the same compound as recited in instant claim 3.
Regarding claims 1-3, 5, and 7, the above reaction scheme anticipates a method of preparing the compound of Formula II recited in instant claim 3, comprising forming a mixture comprising the compound of Formula I recited in instant claim 2, an organic solvent (ethanol), a catalyst (Pd/C), and H2, then reacting the mixture.
Regarding claim 4, the above reaction scheme anticipates wherein the protecting group is benzyl.
Regarding claim 8, room temperature anticipates wherein the temperature is in the range of about -20°C to about 100°C.
Regarding claim 9, the reaction is done at atmospheric pressure.
Regarding claim 12, the reaction time of 5 hours anticipates wherein the reaction time is in the range of about 1 hour to about 48 hours.
Regarding claim 14, the use of a mixture of ethanol and water anticipates wherein the mixture further comprises an aqueous solvent.
The filtration, washing, and drying anticipate the further method steps described in claim 15.
Thus, the above reference anticipates the instantly claimed invention.
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.
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Rajagopalan (J. Med. Chem. 2011, 54, 5048–5058) as applied to claims 1-5, 7-9, 12, and 14-15 above, and further in view of Rylander (Catalytic Hydrogenation in Organic Syntheses, 1979, Academic Press, pp. 1-12).
As discussed supra (see section for rejections under 35 U.S.C. 102), Rajagopalan teaches the below reaction, wherein a mixture comprising compound 4d, an organic solvent, Pd–C, and H2 is formed and reacted to yield compound 2d.
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Rajagopalan does not teach wherein the pressure is elevated.
However, Rylander teaches that temperature, pressure, and agitation can affect both activity and selectivity in catalytic hydrogenation and that in general, as each of these variables is increased over the usual range of operating conditions the rate of hydrogenation increases until some limit is reached (p. 6, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art to utilize the pressure taught by Rajagopalan as a starting point for optimizing the pressure of the reaction since Rajagopalan teaches a reaction at atmospheric pressure and Rylander teaches pressure is a result effective variable; i.e. a variable that achieves a recognized result (increasing the rate of hydrogenation). Therefore, the determination of the optimum or workable pressure would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the reaction in the prior art and the criticality of the claimed reaction pressure, the determination of the optimum or workable reaction pressure given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Rajagopalan (J. Med. Chem. 2011, 54, 5048–5058) as applied to claims 1-5, 7-9, 12, and 14-15 above, and further in view of Dyson (Catal. Sci. Technol., 2016, 6, 3302).
As discussed supra (see section for rejections under 35 U.S.C. 102), Rajagopalan teaches the below reaction, wherein a mixture comprising compound 4d, an organic solvent, Pd–C, and H2 is formed and reacted to yield compound 2d.
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Rajagopalan does not teach wherein the solvent is substantially free of aqueous solvent.
However, Dyson teaches that a solvent may react with a starting material, activating it towards reaction or deactivating it. For example, aqueous solvents may react with CO2 to yield HCO3- and CO32- and these species may undergo hydrogenation rather than the intended reagent (pp. 3306-3307, section 3.3, para. 5)).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the catalytic hydrogenation reaction of Rajagopalan to use a non-aqueous solvent, since Dyson teaches aqueous solvents may deactivate hydrogenation by producing species that H2 will react with over the intended reagent.
Conclusion
Claims 1-5 and 7-20 are rejected.
No claims are allowed.
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/O.D.H./Examiner, Art Unit 1628
/Rayna Rodriguez/Primary Examiner, Art Unit 1628
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