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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on March 17, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Claims 1-4 and 6-13 are currently pending. Claims 1-4 have been amended by Applicants’ amendment filed 03-17-2026. No claims have been canceled by Applicants’ amendment filed 03-17-2026. Claims 6-13 have been added by Applicants’ amendment filed 03-17-2026.
Therefore, claims 1-4 and 6-13 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed August 18, 2022 is a CIP of US Patent Application 16/771,762, filed June 11, 2020, which is a 371 of PCT/RU2017/000424, filed June 16, 2017.
Interview Summary
Applicant contacted the Examiner to set up an interview, where such telephonic interview was conducted between the Examiner and Applicant’s representative Dennis Lazarev on March 16, 2026, where the priority date and potential submission of a corrected ADS was discussed; as well as, potential amendments to the claims.
Product-by-Process
Note that claims 1-4 and 6-13 are determined to be product-by-process claims. The structural elements of the compositions, specifically the combinatorial mixture of antibiotic derivatives comprising: polymyxin B derivatives or gentamicin derivatives or tetracycline derivatives is not considered to limit the mixtures as recited in claims 1, 6 and 10. It is assumed that equivalent mixtures are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. Moreover, even 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 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, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed March 17, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Claim Rejections - 35 USC § 102
The rejection of claims 1-4 is withdrawn under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Farber et. al. (hereinafter “Faber”) (US Patent No. 11191767, issued December 7, 2021; International Application WO2019098869, published May 23, 2019; of record) as evidenced by Yoshizawa et al. (hereinafter “Yoshizawa”) (The EMBO Journal, 1998, 17(22), 6437-648); and Tsigara et al. (hereinafter “Tsigara”) (Dalton Transactions, 2024, 53, 12080-12089).
Due to Applicant’s filing of an updated Application Data Sheet, Farber is not prior art to the instant claims.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1 – 4 is maintained, and claims 6-13 are newly rejected, under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1, 6 and 10 are indefinite for the recitation of the term “the mixture” such as recited in claim 1, line 3. There is insufficient antecedent basis for the term “the mixture” in the claim because claim 1, line 1 recites the term “a combinatorial mixture.” The Examiner suggests that Applicant amend claim 1 to recite, for example, “wherein the combinatorial mixture is obtained by.”
Claim 1 is indefinite for the recitation of the term “polymyxin B” such as recited in claim 1, line 6 because the claims do not particularly point out and distinctly claim the subject matter which the Applicant regards as his invention given that the term “polymyxin B” refers to a mixture of compounds comprising four major components (PB1, PB2, PB3, and PB4) as evidenced by Avedissian (pg. 2, first full paragraph, lines 1-7), such that it is unclear which “polymyxin B” structure is taking part in the combinatorial synthesis reaction recited in claim 1 and, thus, the metes and bounds of the claim cannot be determined.
Claims 1, 6 and 10 are indefinite for the recitation of the term “simultaneously substituted” such as recited in claim 1, line 6 because it is unclear how simultaneous substitution affects the mixture of derivatives; and/or how the structures within the mixture of derivatives as encompassed by claims 1, 6 and 10 is different from the individual structures in a mixture of derivatives that is formed when substitution is carried out step-wise including with the use of protecting groups (or synthesized in some other fashion) and, thus, the metes and bounds of the claim cannot be determined.
Claims 3, 8 and 12 are indefinite for the recitation of the term “halides of carboxylic acids” because it is completely unclear what structures are formed in an undefined combinatorial synthesis reaction comprising a combination of any undefined “halides of carboxylic acids” (e.g., 2,4,6-trimethylbenzoyl chloride, formyl chloride, etc.) including reaction with the multiple different polymyxin B, gentamicin, and/or tetracycline compounds and, thus, the metes and bounds of the claim cannot be determined.
Claim 4, 9 and 13 are indefinite for the recitation of the term “oxirane and propoxy compounds” such as recited in claim 4, lines 11-12 because it is unclear which cyclic alkylating compounds are encompassed by the term “oxirane and propoxy compounds;” including whether all oxiranes (epoxy) and propoxy compounds are cyclic; and/or whether all oxirane and propoxy compounds are cyclic alkylating agents and, thus, the metes and bounds of the claim cannot be determined.
Claim 6 is indefinite for the recitation of the term “gentamicin” such as recited in claim 6, line 3
because the claims do not particularly point out and distinctly claim the subject matter which the Applicant regards as his invention given that the term “gentamicin” refers to a mixture of compounds comprising three major components (gentamicin C1, C1a and C2) and a number of minor components as evidenced by Isoherranen (pg. 1, col 1, first full paragraph, lines 3-5), such that it is unclear which of the “gentamicin” structures is taking part in the combinatorial synthesis reaction recited in claim 6 and, thus, the metes and bounds of the claim cannot be determined.
Claim 10 is indefinite for the recitation of the term “tetracycline” such as recited in claim 10, line 3
because the claims do not particularly point out and distinctly claim the subject matter which the Applicant regards as his invention given that the term “tetracycline” refers to a family of antibiotics, each having a different structure including different functional groups/substitutions on any of rings A, B, C and/or D as evidenced by Chopra (pg. 232, col 1, first partial paragraph; pg. 233, Table 1; and pgs. 234-235, Table 2), such that it is unclear which of the “tetracycline” structures is taking part in the combinatorial synthesis reaction recited in claim 10 and, thus, the metes and bounds of the claim cannot be determined.
Claim 2 is indefinite insofar as they ultimately depend from instant claim 1. Claim 7 is indefinite insofar as they ultimately depend from instant claim 6. Claim 11 is indefinite insofar as they ultimately depend from instant claim 10.
New Objections/Rejections
Claim Objection
Claims 1-4 are objected to because of the following informalities: a clean copy of the claims is requested because Applicant has made a multitude of changes to the claims resulting in significant portions of the recitation being lined-through, such that the claims are visually challenging to the Examiner, and it is difficult for the Examiner to correctly decipher the claimed invention.
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Vaara et al. (hereinafter “Vaara”) (International Application WO2009098357, published August 13, 2009).
Regarding claims 1-4, Vaara teaches that polymyxin B is represented by the following formula:
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wherein commercially available polymyxin B is a mixture, where R-FA is predominantly 6-methyl- octanoyl (6-MOA, in polymyxin B1) but can also be a related fatty acyl such as 6-methylheptanoyl (6-MHA, in polymyxin B2), octanoyl (in polymyxin B3), or heptanoyl (polymyxin B4) (Sakura et al. 2004), such that all of these variants are equally potent against Gram-negatives such as E. coli (Sakura et al. 2004); which is analogous in polymyxin E1 (colistin A) and in circulin A the R-FA is 6-MOA and in polymyxin E2 (colistin B) and in circulin B the R-FA is 6-MHA (interpreted as a mixture of polymyxin B derivatives of claim 1, claims 1-4) (pg. 5, lines 1-10). Vaara teaches that the preparations consist of undefined mixtures of the mono-, di-, tri-, tetra-, and penta-substituted compounds (interpreted as a mixture of polymyxin B derivatives of claim 1, claims 1-4) (pg. 7, lines 5-6). Vaara teaches acylation of the free N-terminal alpha-amino group of the intermediate compounds can be performed using anhydrides such as acetic anhydride (see Example 1 ), propionic anhydride, butyric anhydride, and valeric anhydride by using conditions well-known to a person skilled in the art, wherein N-formylation can be performed by using p-nitrophenyl formate in N-methyl pyrrolidine and conditions well-known to a person skilled in the art, while N-methylation can be performed by using a mixture of formic acid and acetic anhydride in dimethylformamide and conditions well-known to a person skilled in the art (interpreting the anhydrides, formate, and/or acids as chemical modifier 1; and chemical modifier 2; and a mixture of acylated groups using acetic anhydride and malic anhydride, claims 1-4) (pg. 43, lines 7-15). Vaara teaches multiple modifications of polymyxins and multiple polymyxin-like synthetic molecules have been made, and with certain limits they have preserved their biological activity, wherein the modifications comprise but are not limited to those in the side chain, as well as, molecules in which an inherent hydrophobic amino acid residue (such as DPhe or Leu) has been replaced with another hydrophobic amino acid residue or in which the cationic Dab has been replaced with another cationic amino acyl residue, such as Lys, Arg, or ornithine residue (Storm et al. 1997, Tsubery et al. 2000a, Tsubery et al. 2002, US patent publication 2004082505, Sakura et al. 2004, US patent publication 10 2006004185) (interpreted as a mixture of polymyxin B derivatives of claim 1, claims 1-4) (pg. 6, lines 1-10). Vaara teaches that the invention also pertains to polymyxin derivatives of formula (Ill):
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(III)
wherein: A is a polymyxin B or polymyxin E ring moiety; D is R12-C(=O), R12-C(=S) or R12; m1 is O or 1; R1·, R2', and R3' are each independently side chains of natural or unnatural amino acids, alkyl, alkenyl, arylalkyl, aryl, alkoxy, alkoxycarbonyl, aryloxycarbonyl, alkylamino, or alkynyl, wherein at least one of R2’ and R3 comprise a carbamyl, hydroxyl or carboxylate group; and R12 is C1-C4 alkyl, R12' is C1-C5 alkyl, and pharmaceutically acceptable prodrugs and salts thereof, provided that when D is acetyl, butanoyl or pentanoyl, then R3’ is not the side chain of Dab (interpreted as alkylated and/or acylated polymyxin B derivatives, claims 1-4) (pg. 22, 1-25). Vaara teaches that other modifications that result in microbiologically at least partially active compounds comprise but are not limited to alkanoyl esters where the OH-groups of the threonyl residues form esters with alkanoyls such as propionyl and butyryl (US Patent 3,450,687) (interpreted as a mixture of polymyxin B derivatives of claim 1, claims 1-4) (pg. 6, lines 11-14). Vaara teaches that salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane-sulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like (interpreted as halides of carboxylic acids; and derivatives of polymyxin B as encompassed by claim 1, claims 1, 3 and 4) (pg. 32, lines 1-8). Vaara teaches that the R(FA) is selected from the group consisting of carboxylic acid residues, i.e. alkanoyl groups, or alkyl groups, having in total 1 to 5 carbon atoms, wherein R(FA) is preferably selected from the group consisting of methyl, formyl and acetyl residues, while other useful residues can be selected from propanoyl, butanoyl, isobutanoyl, valeroyl, and isovaleroyl residues (interpreted as alkylating agents, claim 1 and 4) (pg. 25, lines 9-13). Vaara teaches that the invention relates to polymyxin derivatives that can be represented by the general formula (V):
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(V)
wherein R4 is an amino acid residue comprising a functional side chain able to cyclize the molecule; R6 and R7 are an optionally substituted hydrophobic amino acid residues; R10 is Leu or any non-hydrophobic amino acid residue; and wherein R 1 may be absent; and wherein R1, R2, R3, R5, R8 and R9 are each independently selected amino acids; and wherein R{FA) is an optionally substituted alkanoyl or alkyl residue, having in total 1 to 5 carbon atoms; or a pharmaceutically acceptable prodrug or salt thereof provided that: (1) when R1 and R2 are absent, R3, R4. R5, RS, and R9 are Dab, R6 is D-Leu, R7 is L-Leu or L-Phe, and R10 is Thr or when R1 and R2 are absent, R3, R4. R5, RB, and R9 are Dab, R6 is D-Phe, R7 is L-Leu, and R10 is Thr, then R(FA) is not an unsubstituted alkanoyl residue; and (2) when R(FA) is acetyl, butanoyl or pentanoyl, then R3 is not Dab (interpreted as polymyxin derivatives that have been multiply alkylated and/or acylated, claims 1-4) (pg. 24, entire page). Vaara teaches that R(FA) can be substituted with substituents readily recognizable by one skilled in the art, provided that R(FA) has no more than 1 to 5 carbon atoms, wherein the substituents can include alkyl, hydroxy and alkoxy, such that alkyl is preferably methyl, ethyl, or propyl, such that alkoxy is preferably methoxy, ethoxy, or propoxy, wherein a person skilled in the art can readily recognize equivalents of these preferred R(FA) residues and substituents thereof (interpreted as cyclic alkylating compounds including propoxy compounds, claim 4) (pg. 25, lines 17-22).
Vaara meets all the limitations of the claims and, therefore, anticipates the claimed invention.
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 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 may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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.
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.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Martynov et al. (hereinafter “Martynov”) (US Patent Application Publication 20140220556, published August 7, 2014) in view of Brown et. al. (hereinafter “Brown”) (US Patent No. 10407467, issued September 10, 2019; published August 4, 2016).
Regarding claims 1, 6 and 10 (all in part), Martynov teaches developing a new method for the design and synthesis of new, highly effective (with effectiveness in the population of near 100%) drugs that are quickly metabolized in the body and decomposed in nature based on dynamic systems (self-organizing and self-adapting to targets) with minimum development expenses (paragraph [0022]).
Martynov teaches "combinatorial supramolecular assemblies" or self-assembled drug, wherein enzymatic cutting of target into small fragments indeed produces one "supramolecular assembly", such that after the partial combinatorial acylation (or alkylation) thousands of fragments appear with different positions of modified groups, which in tum form tens and even hundreds of "supramolecular assemblies"; and combinatorial bioorganic synthesis gives not one, but thousands of different derivatives, which interact not only with target but also with each other (interpreted as combinatorial derivatives; chemical modifier 1; chemical modifier 2, and acylation or alkylation, claim 1) (paragraph [0032]). Martynov teaches in Figure 1 the combinatorial design of modification rate for the target with two amino groups available for substitution: when to one target molecule (i) two molecules of succinic anhydride (ii) are added, their fusion generates only one target molecule with substituted two amide groups (iii), such that when to three molecules of the target four modifier molecules are added, fusion results in three different molecules of the target: two molecules with one substituted group in different positions and one fully substituted molecule (iv) (interpreted as combinatorial synthesis reactions; chemical modifier 1; chemical modifier 2, and acylation or alkylation, claim 1) (paragraph [0034]; and Figure 1). Figure 1 is shown below:
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Martynov teaches that the obtained biopolymer target fragments are modified through changing their charge to the opposite charge through acylation with anhydrides of dicarbonate acids or alkylation with halogen carbon acids (interpreted as alkylation; acylation; anhydrides; and halides of carboxylic acids, claims 1, 6 10) (paragraph [0023], lines 15-19). Martynov teaches that acylation of terminal amino groups, lysines, and histidines, by means of various agents, among which the simplest are anhydrides of carboxylic (and polycarboxylic) acids: acetic, succinic, and maleic acids (interpreted as acylation of NH2 and NHR groups; and encompassing acetic anhydride, succinic anhydride, and maleic anhydride, claims 2, 7 and 11) (paragraph [0015]). Martynov teaches that the hydroxyl groups of amino acids like threonine and serine can be acylated (interpreted as modifying OH groups, claim 1) (paragraph [0071], lines 11-12).
Regarding claims 2, 7 and 11, Martynov teaches that acylation of terminal amino groups, lysines, and histidines, by means of various agents, among which the simplest are anhydrides of carboxylic (and polycarboxylic) acids: acetic, succinic, and maleic acids (interpreted as acylation of NH2 and NHR groups; and encompassing acetic anhydride, succinic anhydride, and maleic anhydride, claims 2, 7 and 11) (paragraph [0015]). Martynov teaches that interferon is a low-molecular protein with a molecular weight of 8 kDa, where it contains eight fragments of lysine and three fragments of histidine, which are capable of being acylated by succinic (SA) and aconite (AA) anhydrides; and that acylation is provided by anhydrides of polycarboxylic acid (interpreted as encompassing succinic anhydride, aconitic anhydride, etc., claims 2, 7 and 11) (paragraphs [0070]; and [0126], claim 16). Martynov teaches that the modifications can significantly expand the activity spectrum of bacteriocins and increase their protein break-down stability; which will allow new peptide antibiotics to be created on their basis on an industrial scale (interpreted as antibiotics, claims 1, 6, and 10) (paragraph [0067], lines 6-10). Martynov teaches that the modification rate is determined by the formulas: m = (2"-1), where:
m – number of molecules or moles of the biopolymer target, that must be modified to obtain the maximum amount of various derivatives of the biopolymer target, n-quantity of the nitrogen-containing groups that are positively charged and available for modification in the one biopolymer target; and k = n2n-1), where: k-number of moles of modifier, that is necessary for the combinatorial modification of the biopolymer target containing n groups available for modification (interpreted as molar ratios, claim 1, 6, and 10) (paragraphs [0038]-[0043]).
Regarding claims 3, 4, 8, 9, 12 and 13, Martynov teaches that the obtained biopolymer target fragments are modified through changing their charge to the opposite charge through acylation with anhydrides of dicarbonate acids or alkylation with halogen carbon acids (interpreted as alkylation; acylation; anhydrides; and halides of carboxylic acids, claims 1, 6 10) (paragraph [0023], lines 15-19). Martynov teaches that alkylation is provided by halogen-derivatives carboxylic acids (interpreted as alkylation; and halides of carboxylic acids, claims 1, 6, 10) (paragraph [0126], claim 17).
Martynov does not specifically exemplify polymyxin B, tetracycline, and gentamicin (claims 1, 6 and 10, all in part).
Regarding claim 1 (in part), Brown teaches polymyxin compounds having an N terminal group that contains one, two or three hydroxyl groups and/or one, two, or three amino groups having formulas (I) and (II), for use in combination treatment with a second active agent, such as rifampicin, gentamicin and/or tetracycline, such as for the treatment of microbial infection (interpreted as encompassing the polymyxin B derivatives of claim 1) (Abstract; col 5, lines 29-32; col 7, lines 20-22; and col 8, lines 14-15 and 48). Brown teaches that polymyxin B has the structure shown below:
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(interpreted as polymyxin B, claim 1) (col 14, lines 31-39). Brown teaches that the compounds of the invention of formula (I) and (II) are N terminal derivatives of the polymyxin series of compounds including polymyxin B, wherein the core of the compound of the invention is a deacylated version of a polymyxin compound or a nonapeptide version of a polymyxin compound, such as deacylated polymyxin B nonapeptide (PMBN) or deacylated colistin, wherein the compound of formula (I) is represented thus:
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(col 9, lines 43-67 through col 13, line 21). Brown teaches that the polymyxin compound of formula (II) is shown below:
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(interpreted as encompassing the polymyxin B derivatives of claim 1) (claim 1, col 176, lines 18-67 through col 178, line 60).
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Moreover, it is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of synthesizing polymyxin B derivatives as exemplified by Brown, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of synthesizing combinatorial supramolecular assemblies that can overcome the ability of microorganisms to adapt to drugs such as antibiotics by obtaining biopolymer target fragments that are modified by acylation and/or alkylation as disclosed by Martynov to include polymyxin B and/or polymyxin B derivatives designed and administered to treat microbial infections as taught by Brown, with a reasonable expectation of success in designing and synthesizing thousands of different modified polymyxin B derivatives as effective new drugs for the treatment of microbial infections; in synthesizing polymyxin B derivatives that can be used in combination treatments for microbial infection; and/or in producing new antibiotic compounds that can overcome the high adaptability of microorganisms to a drug.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103 as obvious over the art.
Claims 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Martynov et al. (hereinafter “Martynov”) (US Patent Application Publication 20140220556, published August 7, 2014) in view of Levy et. al. (hereinafter “Levy”) (US Patent Application 20040063674, published April 1, 2004).
The teachings of Martynov as applied to claims 6-9 are described supra.
Martynov does not specifically exemplify tetracycline derivatives (claim 6, in part).
Regarding claim 6 (in part), Levy teaches tetracycline compounds having formula (I) having a target therapeutic activity as shown below:
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wherein R2, R2', R4', and R4" are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; R6 and R6' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R7, R8 and R9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, and thionitroso (interpreted as tetracycline derivatives as encompassed by claim 6 including alkylated and acylated derivatives, claim 6) (paragraphs [0010]-[0012]; and [0015]-[0019]). Levy teaches a method for treating a disease with a tetracycline compound having a target therapeutic activity (paragraph [0043]). Levy teaches that the term "tetracycline compound" includes substituted tetracycline compounds or compounds with a similar ring structure to tetracycline, wherein examples of tetracycline compounds include: chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, chelocardin, rolitetracycline, lymecycline, apicycline; clomocycline, guamecycline, meglucycline, mepylcycline, penimepicycline, pipacycline, etamocycline, penimocycline, etc. including other derivatives and analogues comprising a similar four ring structure are also included (See Rogalski, "Chemical Modifications of Tetracyclines," the entire contents of which are hereby incorporated herein by reference); and Table 1 depicts tetracycline and several known other tetracycline derivatives (interpreted as tetracycline derivatives as encompassed by claim 6 including alkylated and acylated derivatives, claim 6) (paragraph [0045]). Levy teaches that the tetracycline compounds may or may not have antibacterial or antiinfective activity (paragraph [0047], lines 4-5).
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Moreover, it is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of synthesizing tetracycline derivatives as exemplified by Levy, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of synthesizing combinatorial supramolecular assemblies that can overcome the ability of microorganisms to adapt to drugs such as antibiotics by obtaining biopolymer target fragments that are modified by acylation and/or alkylation as disclosed by Martynov to include antibiotics such as tetracycline and/or tetracycline derivatives useful for treating disease as taught by Levy, with a reasonable expectation of success in synthesizing thousands of modified tetracycline derivatives having a target therapeutic activity; and/or in producing effective new drugs for the treatment of diseases including derivatives having antibacterial and/or antiinfective activity.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103 as obvious over the art.
Claims 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Martynov et al. (hereinafter “Martynov”) (US Patent Application Publication 20140220556, published August 7, 2014) in view of Aggen et. al. (hereinafter “Aggen”) (US Patent No. 9688711, issued June 27, 2017; published December 22, 2016).
The teachings of Martynov as applied to claims 10-13 are described supra.
Martynov does not specifically exemplify gentamicin derivatives (claim 10, in part).
Regarding claim 10 (in part), Aggen teaches aminoglycoside compounds having formula (I) having antibacterial activity, and for the treatment of bacterial infections, wherein formula (I) is shown below:
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246
362
media_image11.png
Greyscale
(I)
wherein: Q1 is hydrogen,
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96
322
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or
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98
122
media_image13.png
Greyscale
Q2 is hydrogen, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl,
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media_image14.png
98
316
media_image14.png
Greyscale
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media_image15.png
96
124
media_image15.png
Greyscale
Q3 is hydrogen, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -C(NH)NR4R5 , -(CR10R11)pR12,
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98
316
media_image14.png
Greyscale
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media_image15.png
96
124
media_image15.png
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wherein each R9 is, independently, hydrogen or methyl (interpreted as a mixture of gentamicin derivatives including alkylated and/or acylated OH, NH2 and NHR, claim 10) (col 4, lines 26-67; and col 5, lines 1-40). Aggen teaches in Table 1, a minimum inhibitory concentration (MIC) assay protocol for determining MIC for compounds 1-108 (interpreted as derivatives of gentamicin, claim 10) (col 285, lines 40-43 and 60-67 through col 287, line 25; and Table 1). Aggen teaches that as shown in Table 2, representative compounds and known aminoglycosides such as gentamicin and amikacin were tested for in vivo efficacy in a murine septicemia model of infection using E. coli and P. aeruginosa QC bacterial strains (interpreted as derivatives of gentamicin, claim 10) (col 287, lines 33-37; and col 288, Table 2). Table 2 is shown below:
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278
416
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Aggen teaches that Table 3 shows certain di-substituted sisomicin derivatives, certain mono-substituted sisomicin derivatives and sisomicin were tested against QC and aminoglycoside resistant bacterial strains containing confirmed resistance mechanisms that covalently modify the 6'-amino group in many aminoglycosides (interpreted as gentamicin derivatives multiply substituted, claim 10) (col 288, lines 28-33; and col 288-292, Table 3).
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Moreover, it is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of synthesizing aminoglycoside derivatives including gentamicin derivatives as exemplified by Aggen, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of synthesizing combinatorial supramolecular assemblies that can overcome the ability of microorganisms to adapt to drugs such as antibiotics by obtaining biopolymer target fragments that are modified by acylation and/or alkylation as disclosed by Martynov to include aminoglycoside antibiotics including gentamicin and/or gentamicin derivatives as taught by Aggen, with a reasonable expectation of success in synthesizing thousands of different gentamicin derivatives having antibacterial activity; and/or for use in preventing and/or treating bacterial infections.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103 as obvious over the 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 1-4 and 6-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claim 1 of U.S. Patent No. 11229622 – directed to a combinatorial quercetin derivative; wherein the combinatorial quercetin derivative is obtained by a combinatorial modification of quercetin by at least a first alkylating and/or acylating modifier and a second alkylating and/or acylating modifier, wherein the first alkylating and/or acylating modifier and the second alkylating and/or acylating modifiers are selected from the group consisting of succinic anhydride, acetic anhydride, maleic anhydride, aconitic anhydride, glutaric anhydride, phthalic anhydride, acetic anhydride, formic acid ethyl ester, monochloroacetic acid, propiolactone, ethylene oxide, methyl chloride, ethyl chloride, and propyl chloride; provided that the combinatorial modification of quercetin is performed using a molar ratio of quercetin: first modifier: second modifier of 92:155:155; and the resulting combinatorial quercetin derivative is used as a mixture, without separation into individual components (claim 1).
Claims 1-3 of U.S. Patent No. 11191767 – directed to a pharmaceutical composition, including histone deacetylase inhibitors, dipyridamole and other phosphodiesterase inhibitors, as well as pharmaceutically acceptable excipients, wherein it also contains unseparated mixture of dipyridamole combinatorial derivatives obtained by means of simultaneous modification by at least two covalent modifying agents selected from succinic anhydride, monochloroacetic acid, malic anhydride, acetic anhydride, propionic anhydride, butane anhydride, acetic-propionic anhydride, acetic-butane anhydride, glutaric anhydride, phthalic anhydride, cis-aconitic anhydride, trans-aconitic anhydride, citric anhydride, isolemic anhydride, acetyl chloride, acetyl fluoride, propionyl chloride, butyroyl chloride, and ethoxyoxalyl monochloride (claim 1).
Although the claims at issue are not identical, they are not patentably distinct from each other because: the instant claims, and the claims of U.S. Patent Nos. 11229622 and 11191767 encompass a combinatorial mixture of antibiotic derivatives including polymyxin B derivatives, tetracycline derivatives, and gentamicin derivatives.
Applicant is respectfully reminded that the claims must particularly point out and distinctly claim the subject matter which the Applicant regards as his invention. Instant claims 1, 6 and 10 are directed to mixtures of polymyxin B derivatives, tetracycline derivatives, and gentamicin derivatives; however, it is completely unclear what specific structures and/or what specific mixture of structures are encompassed by the claims.
Conclusion
Claims 1-4 and 6-13 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684