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 .
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.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 May 6, 2026 has been entered.
The amendment filed May 6, 2026 has been entered. Claims 26 and 29 have been amended and claims 4, 6, 9, 18-23, 27-28, and 31-32 are cancelled. This application is the U.S. national phase of International Application No. PCT/US2021/027397, filed on April 15, 2021, which claims the benefit of United States Provisional Patent Application No. 63/011,398, filed April 17, 2020.
Applicant’s arguments filed May 6, 2026 were fully considered but they were not persuasive. Rejections and response to arguments are addressed below.
Claims 1-3, 5, 7-8, 10-17, 24-26, and 29-30 are pending in this application.
Claim Interpretation
Regarding claims 1 and 3: Claim 1 recites inter alia “An oligomer comprising (a) from about 8 to about 25 monomer units of formula (I)…. (b) from 0 to about 24 monomer units of formula (II)….”. Claim 3 recites inter alia, “….wherein the oligonucleotide comprises a sum of from about 12 to about 25 monomer units of formula (I) and formula (II).”. Given that formula (II) can be 0, claim 3 also includes oligomers wherein the sum is based upon the addition of “0” monomer units of formula (II). For example, 12 units of formula (I) plus 0 units of formula (II) equals a sum of 12 monomer units of formula (I) and formula (II).
Drawings
The drawings are objected to because:
Figure 5B has overlapping structures rendering subscripts illegible:
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.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “wherein the substituents on the tetrahydrofuranyl group have a trans configuration;”. The claim should be amended to specify the 3 and 4 positions to avoid any confusion, similar to claims 26 and 29.
Appropriate correction is required.
Modified 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 1-3, 5, 7-8, 10, 16-17, 25-26, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Swaminathan (WO 93/24507, cited in previous action) in view of Pokorski (J. Am. Chem. Soc., 2004, IDS filed October 13, 2022) as evidenced by Bacon (US 2016/0176870, cited in previous action).
Regarding claims 1-3, 5, 10, 16-17: Swaminathan teaches oligomers which comprise the presence of one or more nucleomonomers exemplified by formula (V):
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where B is a purine or pyrimidine base or an analogous form thereof; X1 is S, O, SO, SO2, CH2, CHF, CF2, NR or CH lower alkyl including CH-methyl, CH-ethyl, CH-propyl and CH-butyl, provided that adjacent X1 are not both O(pg. 13, lines 16-19, pg. 14, lines 20-25, pg. 15, lines 1-13, drawings pg. 14, figure 8). Although X1 can be selected from multiple options, a specific claim of the reference recites that in formula (V) X is O (pg. 52, lines 1-2, claim 6). Thus, a person of ordinary skill would be drawn to select O from the list of possible alternatives, leading to an oligomer represented by formula (I) as recited by instant claim 1. Pyrimidines include uracil and cytosine and purines include adenine and guanine, as well as analogs thereof (pg. 21, lines 12-21). Swaminathan teaches oligomers containing 2 to 30 nucleomonomers are preferred (pg. 16, lines 16-17). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (See MPEP 2144.05 (I)). All monomers that are used for incorporation into oligomers are protected at the amino terminus using groups commonly employed in peptide synthesis methods, such as t-butylcarbamates (tBOC) and FMOC (pg. 33, lines 18-21). Terminal oligomer moieties such.as -NH2 or -COOH can be blocked or derivatized using standard procedures of routine use (i.e. amino terminus and carboxy terminus, wherein amino terminus is -NH2 and carboxy terminus is -COOH, as recited by instant claims 10 and 16, pg. 31, lines 12-14). The oligomers of the invention are for binding to complementary nucleic acid target sequences (as recited by instant claim 17, pg. 12, lines 1-8). Swaminathan is directed towards the use of constrained nucleomonomers that are able to bind to a target nucleic acid in a sequence specific manner (pg. 2, lines 15-21).
Swaminathan does not teach the substituents on the tetrahydrofuranyl group have a trans configuration.
However, Pokorski teaches that oligomers comprising (S,S)-trans cyclopentyl units significantly increases binding affinity and sequence specificity to complementary DNA (abstract). Pokorski teaches that the (S,S) stereochemistry is more compatible than (R,R) in PNA-DNA duplexes (pg. 15073, col. 1, para. 2). Pokorski teaches both ring size and stereochemistry must restrict the PNA to access only the range of dihedral angles necessary for binding, while excluding conformations that are irrelevant to duplex formation (pg. 15073, col. 1, para. 2).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the oligomer of Swaminathan by (3S,4S)-trans stereochemistry into the constrained backbone as taught by Pokorski. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success given that the art establishes the trans configuration is preferred in 5 membered rings in these types of oligomers, in order to improve the ability to bind to DNA sequences.
Regarding claims 7-8: As discussed above, Swaminathan renders obvious the oligomer of instant claim 1. Swaminathan teaches oligomers containing 2 to 30 nucleomonomers are preferred (pg. 16, lines 16-17). Swaminathan further teaches cyclopentyl backbones are contemplated as an alternative in the oligomer (drawings pg. 19, figure 13). Swaminathan suggests the oligomer can comprise one or more invention nucleomonomers disclosed (pg. 13, lines 16-19). Swaminathan directly compares the spatial comparison of an amide linked oligomer with an amide linked oligomer composed of linked cyclopentyl monomers (pg. 19, lines 33-35, drawings pg. 19, figure 13).
Swaminathan does not explicitly teach an oligomer comprising cyclopentyl and tetrahydrofuran backbones as recited by instant claims 7-8.
However, Pokorski teaches that oligomers comprising one or more nucleomonomers, such as the inclusion of cyclopentyl, is a known practice in the art (pg. 15068, top of page, figure 1,). Pokorski teaches that combinations of monomers can impact the stability of the oligomers or modulate binding affinity (pg. 15068, col. 1).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the oligomer of Swaminathan by incorporating different backbone monomers into the oligomer, such as cyclopentyl (i.e. formula (III) as recited by instant claims 7-8), as taught by Pokorski. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success given that the art establishes mixed oligomers are known in the art, and incorporation of constrained monomers, or other monomers can modulate binding affinity and stability. A person of ordinary skill in the art would be capable of determining the appropriate amount of individual monomers in the oligomer through routine optimization, as the art establishes that by substituting monomers, stability and sequence specificity can be modulated (See MPEP 2144.05 (II)).
Regarding claim 25: Swaminathan teaches, for therapeutic applications, the oligomer active ingredient is generally combined with a carrier such as a diluent or excipient (pg. 42, lines 4-13)
Regarding claims 26 and 29-30: As discussed above Swaminathan and Pokorski render obvious the oligomer of instant claim 6 with trans stereochemistry.
Swaminathan further teaches the synthetic scheme for preparing a monomer corresponding to formula (V) (pg. 33, lines 7-16). Swaminathan teaches synthesis of the monomer described above in figure 8, would be conducted in a manner analogous to the synthetic schemes shown in figures 5 and 6, with synthesis of compounds analogous to compound 26 starting from protected, substituted ethylene diamine having the ring constraints corresponding to those shown in Formulas V (pg. 33, lines 10-16). Figure 5 is directed towards the synthesis of a hydroxymethyl monomer:
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wherein the hydroxymethyl group is protected with a silicon group(pg. 19, lines 12-13, drawings pgs. 8-9, figures 5.1-5.2, drawings pg. 9, compound 26). Replacing the hydroxymethyl ethylene diamine with the appropriate ethylene diamine group as suggested by Swaminathan would lead to the following monomer structure:
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wherein R1 is Fmoc (a nitrogen protecting group), R2 is H, and B is thymine (a nucleobase) (with appropriate stereochemistry as suggested by Pokorski, rendering obvious the compounds of claims 29-30). Additionally, as discussed previously, Swaminathan teaches monomers that are used for incorporation into oligomers are protected at the amino terminus using groups commonly employed in peptide synthesis methods, such as t-butylcarbamates (tBOC) and FMOC (pg. 33, lines 18-21). Thus, R1 can alternatively be a tert-butylcarbamate. Bacon demonstrates that the appropriate trans (3S,4S) tBOC diethylene diamine reagent is known in the prior art:
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(pg. 74, col. 2, top of page, pg. 75, col. 1, para. 0660). With respect to instant claim 26 which can be a considered a precursor the compounds represented by instant claims 29-30, Swaminathan teaches that compound 26 discussed above is synthesized in part utilizing the following reaction:
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(drawings pg. 8, figure 5.1, bottom of page). Similarly, replacing the hydroxymethyl ethylene diamine with the appropriate ethylene diamine group as suggested by Swaminathan would lead to the following precursor monomer structure:
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wherein R1 is Cbz (a nitrogen protecting group), and R2 is ethyl (a c2alkyl), rendering obvious the compound of claim 26.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Swaminathan (WO 93/24507, cited in previous action), Pokorski (J. Am. Chem. Soc., 2004, IDS filed October 13, 2022), and Bacon (US 2016/0176870, cited in previous action) as applied to claims 1-3, 5-8, 10, 16-17, 25-26, and 29-30 above in view of Liu (WO 2010/027326, cited in previous action).
Regarding claim 11: As discussed above, Swaminathan, Pokorski, and Bacon render obvious the oligomer with appropriate stereochemistry an amino terminus as recited by instant claims 1, 6, and 10. Swaminathan teaches the oligomers of the invention can be used as diagnostic reagents to detect the presence or absence of the target nucleic acid sequences to which they specifically bind (pg. 43, lines 23-26). The enhanced binding affinity of the invention oligomers is an advantage for their use as primers and probes (pg. 43, lines 26-28). Diagnostic tests can be conducted by hybridization through either double or triple helix formation which is then detected by conventional means (pg. 43, lines 29-31). For example, the oligomers can be labeled using radioactive, fluorescent, or chromogenic labels and the presence of label bound to solid support detected (pg. 43, lines 31-34). Swaminathan teaches that the amino terminus is suitable for coupling to a label, such as a radioisotope, enzyme, or chromophore (pg. 16, lines 20-28). Swaminathan directly compares the spatial comparison of an amide linked oligomer with an amide linked oligomer composed of linked cyclopentyl monomers (pg. 19, lines 33-35, drawings pg. 19, figure 13).
Swaminathan does not teach wherein the oligomer comprises the dye fluorescein at the amino terminus as recited by instant claim 11.
However, Liu teaches the preparation of peptide nucleic acid molecules comprising peptide acid monomers with a terminal amine group (abstract). Liu teaches the peptide nucleic acid molecules can effectively by labeled by fluorescein at the N-terminus for cellular uptake studies (pg. 39, para. 0123).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the oligomer of Swaminathan by conjugating the amino terminus to the dye fluorescein as taught by Liu. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes this as a known modification of these types of oligomers for the purpose of performing cellular uptake studies in establishing oligomer uptake. It is prima facie obvious to apply a known technique to a known device (method, or product) ready for improvement to yield predictable results (See MPEP 2143 (ID)).
Claims 12-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Swaminathan (WO 93/24507, cited in previous action), Pokorski (J. Am. Chem. Soc., 2004, IDS filed October 13, 2022), and Bacon (US 2016/0176870, cited in previous action) as applied to claims 1-3, 5-8, 10, 16-17, 25-26, and 29-30 above in view of Paudyal (Nucl. Med. Biol., 2013, cited in previous action).
Regarding claims 12-13 and 15: As discussed above, Swaminathan, Pokorski, and Bacon render obvious the oligomer with appropriate stereochemistry an amino terminus as recited by instant claims 1, 6, and 10. Swaminathan teaches the oligomers of the invention can be used as diagnostic reagents to detect the presence or absence of the target nucleic acid sequences to which they specifically bind (pg. 43, lines 23-26). The enhanced binding affinity of the invention oligomers is an advantage for their use as primers and probes (pg. 43, lines 26-28). Diagnostic tests cab be conducted by hybridization through either double or triple helix formation which is then detected by conventional means (pg. 43, lines 29-31). For example, the oligomers can be labeled using radioactive, fluorescent, or chromogenic labels and the presence of label bound to solid support detected (pg. 43, lines 31-34). Swaminathan teaches that the amino terminus is suitable for coupling to a label, such as a radioisotope, enzyme, or chromophore (pg. 16, lines 20-28).
Swaminathan does not teach wherein the oligomer comprises 1,4,7,10-tetraazacyclododecane-N, N’, N”, N”’-tetraacetic acid (DOTA) in combination with 64Cu at the amino terminus with a linker comprising
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wherein m is 2 as recited by instant claim 12-13 and 15.
However, Paudyal teaches a method for monitoring breast cancer therapy by determining HER2 mRNA in malignant breast cancer cells with positron emission tomography (abstract). Paudyal teaches the synthesis of a radionuclide-chelator-peptide nucleic acid-peptide agents comprising a Cu-64-DOTA as the radiolabel-chelator with a
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linker, wherein m is 2, conjugated to a peptide nucleic acid (PNA) at the amino terminus (pg. 2, introduction, paras. 4, pg. 13, scheme 1). The conjugate has the following structure
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(pg. 13, scheme 1).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the oligomer of Swaminathan by conjugating the amino terminus to a radiolabel as demonstrated by Paudyal. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as the art establishes this as a known modification of these types of oligomers for the purpose of acting as hybridizing diagnostic agents as suggested by Swaminathan and taught by Paudyal. It is prima facie obvious to use a known technique to improve similar devices (methods, or products) in the same way (See MPEP 2143 (IC)).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Swaminathan (WO 93/24507, cited in previous action), Pokorski (J. Am. Chem. Soc., 2004, IDS filed October 13, 2022), and Bacon (US 2016/0176870, cited in previous action) as applied to claims 1-3, 5-8, 10, 16-17, 25-26, and 29-30 above in view of Gildea (US 6,326,479, cited in previous action).
Regarding claim 14: As discussed above, Swaminathan, Pokorski, and Bacon render obvious the oligomer with appropriate stereochemistry an amino terminus as recited by instant claims 1, 6, and 10. Swaminathan teaches oligomers of any length may be prepared including 10-mers (10 nucleomonomers), 20-mers, 50-mers, 100-mers, 200-mers, 500-mers or oligomers of greater length (pg. 16, lines 13-16). Swaminathan teaches oligomers containing 2 to 30 nucleomonomers are preferred (pg. 16, lines 16-17). Swaminathan teaches oligomers are two or more nucleomonomers covalently coupled to each other by a linkage or substitute linkage moiety (i.e. a linker, pg. 23, lines 22-24). Thus, an oligomer can have as few as two covalently linked nucleomonomers (a dimer) (i.e. a linker, pg. 23, lines 24-26).
They do not explicitly teach wherein the oligomer is a conjugated through the amino terminus with a second oligomer comprising about 12 to about 25 monomer units of formula (I).
However, Gildea teaches methods for modulating the aqueous solubility of peptide nucleic acid (PNA) polymers (abstract). Gildea teaches for most applications an oligomer of 12-15 is optimal (col. 2, lines 58-59). Longer PNA oligomers, depending on the sequence, tend to aggregate and are difficult to purify and characterize (col. 2, lines 59-61). A number of modifications have been made to peptide nucleic acids in order to improve their aqueous solubility or minimize polymer self-aggregation, which include modification of the backbone (col. 3, lines 10-12, 17-20). For example, a PNA may be modified by condensation of a suitable carboxylic acid moiety with the N-terminus or side chain nucleophilic group ( e.g. amine, hydroxyl or thiol) of the polymer during chemical assembly (col. 16, lines 56-60). Alternatively, if polymer assembly is to be continued after N-terminal modification or labeling, typically a suitably protected amino acid synthon is used so that the amino group of this synthon can be used to further extend the polymer (col. 16, lines 61-65). Gildea teaches the use of branched protected amino acid synthons (i.e. a linker) which can be incorporated at any position of the polymer sequence without terminating polymer assembly in order to enhance solubility and reduce polymer aggregation (col. 17, lines 3-12). When modifying PNAs it is preferable to use suitably protected amino acids which will maintain the spacing between nucleobases (col. 29, lines 38-40). Preferred modifying moieties can be inserted within the polymer without disrupting the nucleobase spacing and thereby, presumably, not alter the hybridization efficiency of the oligomer to a target nucleic acid (col. 29, lines 40-43).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to further modify the oligomer of Swaminathan by incorporating a linker at the amino-terminus to combine oligomer subunits as taught by Gildea. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to improve solubility and reduce aggregation thereby facilitating the production of longer oligomers with similar makeup. Wherein Swaminathan teaches Swaminathan teaches oligomers containing 2 to 30 nucleomonomers are preferred but can be greater in length, oligomer subunits combining 12+12 (24 total) nucleomonomers of formula (I) separated by a linker are encompassed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (See MPEP 2144.05 (I)).
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Swaminathan (WO 93/24507, cited in previous action), Pokorski (J. Am. Chem. Soc., 2004, IDS filed October 13, 2022), and Bacon (US 2016/0176870, cited in previous action) as applied to claims 1-3, 5-8, 10, 16-17, 25-26, and 29-30 above in view of Ueno (PLoS ONE, 2014, cited in previous action).
Regarding claim 24: As discussed above, Swaminathan, Pokorski, and Bacon render obvious the oligomer with appropriate stereochemistry an amino terminus as recited by instant claims 1, 6, and 10. Swaminathan teaches the oligomers of the invention can be used as diagnostic reagents to detect the presence or absence of the target nucleic acid sequences to which they specifically bind (pg. 43, lines 23-26). The enhanced binding affinity of the invention oligomers is an advantage for their use as primers and probes (pg. 43, lines 26-28). Diagnostic tests cab be conducted by hybridization through either double or triple helix formation which is then detected by conventional means (pg. 43, lines 29-31).
Swaminathan does not teach wherein the oligomer has the specific sequence AGTCTGATAAGCTA as recited by instant claim 24.
However, Ueno teaches the use of DNA probes for diagnostic testing of microRNAs, which are biomarkers for cancer and other human diseases (abstract). Ueno specifically teaches the use of a capture probe comprising the sequence AGTCTGATAAGCTA for the detection of miR-21 (pg. 3, col. 1, para. 1).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the oligomer of Swaminathan by using the base sequence AGTCTGATAAGCTA as taught by Ueno. A person of ordinary skill in the art would have the motivation to do so with a reasonable expectation of success as the art establishes this sequence can capture miR-21 for the purpose of diagnostic testing of microRNAs, and Swaminathan establishes that the oligomers can be effectively used for this purpose.
Response to Arguments
Applicant’s arguments and the declaration of Appella filed May 6, 2026 have been fully considered but they are not persuasive.
On page 10 of Applicant’s remarks, Applicant argues the art relied upon fails to suggest the presently claimed invention to those of ordinary skill in the art for a conformationally restrained oligomer that is able to enter cells without assistance from known cell-delivery agents (para. 2).
However, as discussed above, Swaminathan teaches tetrahydrofuran backbone oligomers (achiral), and teaches that the therapeutic potential of oligomers is generally enhanced by modifications that increase oligomer uptake by cells or reduce the rate of metabolism by cells or serum (pg. 12, lines 21-27).
On page 10 of Applicant’s remarks, Applicant argues Swaminathan is a weak reference with very little meritorious disclosure (para. 2). Applicant argues that Swaminathan was abandoned and discloses a synthesis of compound 23 and it does not disclose or suggest a method to make a compound having a cyclic ether ring has shown in formula (V) (para. 2). Applicant argues the Office goes to great lengths to cite various secondary references in an attempt to make a prima facie case of obviousness for the claimed invention (para. 3).
However, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments (See MPEP 2123 (I)). Additionally, Swaminathan does suggest a method for making a compound having a cyclic ether ring as shown in formula (V): “Swaminathan further teaches the synthetic scheme for preparing a monomer corresponding to formula (V) (pg. 33, lines 7-16). Swaminathan teaches synthesis of the monomer described above in figure 8, would be conducted in a manner analogous to the synthetic schemes shown in figures 5 and 6, with synthesis of compounds analogous to compound 26 starting from protected, substituted ethylene diamine having the ring constraints corresponding to those shown in Formula V (pg. 33, lines 10-16). Additionally reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention (See MPEP 2145 (V)).
On page 11 of Applicant’s remarks, Applicant argues there must be some teaching suggestion, or incentive to make the composition made by Applicant (para. 2). Applicant argues the office has relied upon hindsight reasoning to arrive at the claimed invention and would not have been able to predict the properties of independent cell uptake without the additional use of a known cell-delivery agent (para. 3). On page 12 of Applicant’s remarks, Applicant argues the office utilized hindsight reconstruction to arrive at the claimed invention.
However, any judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper (See MPEP 2145 (X)(A)). There is no requirement that an express, written motivation to combine must appear in prior art references before a finding of obviousness. As discussed above Swaminathan teaches tetrahydrofuran backbone oligomers (achiral), and teaches that the therapeutic potential of oligomers is generally enhanced by modifications that increase oligomer uptake by cells or reduce the rate of metabolism by cells or serum (pg. 12, lines 21-27). Thus it cannot be considered to be unexpected that the THF backbone oligomers of Swaminathan exhibit improved cell uptake. Pokorski is relied upon for teaching both the introduction of other PNA molecules in the oligomers, a known technique in the art, as well as the introduction of trans configuration in cyclic backbones, of which is known in the art to improve binding to nucleic acids (i.e. motivation).
On page 13 of Applicants response, Applicant argues Appella Declaration 2 filed May 6, 2026, further demonstrates the error in the aforementioned obviousness rejections (last para.). The declaration of Appella, filed May 6, 2026, argues that the position of the Examiner is that Swaminathan discloses the following reaction:
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(pgs. 4-5, section 7). The declaration of Appella argues that such a transformation is not possible as the compound produced by such a reaction would have an extra CH2 group to the oxygen labeled 1. On page 5 of the declaration (section 8), the declaration of Appella argues that the actual synthetic routes to Formula V do not use any of the key synthetic steps described in Swaminathan, and it is clear that no synthetic chemist could use the synthetic approaches to accomplish the transformation from 26 to Formula V.
However, Swaminathan (in combination with other references) renders obvious a method in which ethylene-diamine reagents are substituted for one another. In the cited case, the specific ethylene-diamine reagent in compound 26 is one that possesses a hydroxymethyl protected silicon group. Swaminathan teaches that synthesis of other monomers would follow a manner analogous to the synthetic scheme, by using alternative ethylene diamine reagents. The specific synthesis of compound 23 in Swaminathan is based upon the modification of L-serine into an ethylene diamine-type reagent, wherein the carboxylic acid group of L-serine is converted into the silicon protected compound 23 (See drawings, pg. 8, figure 5-1). Swaminathan teaches the following structure:
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(wherein X1 can be O), which does not have a silicon-protected hydroxymethyl group (drawings, figure 8). As stated above,
“Swaminathan further teaches the synthetic scheme for preparing a monomer corresponding to formula (V) (pg. 33, lines 7-16). Swaminathan teaches synthesis of the monomer described above in figure 8, would be conducted in a manner analogous to the synthetic schemes shown in figures 5 and 6, with synthesis of compounds analogous to compound 26 starting from protected, substituted ethylene diamine having the ring constraints corresponding to those shown in Formula V (pg. 33, lines 10-16). “Figure 5 is directed towards the synthesis of a hydroxymethyl monomer:
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wherein the hydroxymethyl group is protected with a silicon group(pg. 19, lines 12-13, drawings pgs. 8-9, figures 5.1-5.2, drawings pg. 9, compound 26). Replacing the silicon protected hydroxymethyl ethylene diamine with the appropriate ethylene diamine group as suggested by Swaminathan would lead to the following monomer structure:
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wherein R1 is Fmoc (a nitrogen protecting group), R2 is H, and B is thymine (a nucleobase) (with appropriate stereochemistry as suggested by Pokorski, rendering obvious the compounds of claims 29-30).”.
Although compound 26 possesses a silicon protected hydroxymethyl group, this group is a part of the starting ethylene diamine reagent, and thus would not be present in the structure if replaced with the appropriate ethylene diamine reagent if one was following the synthesis of other compounds encompassed by Swaminathan. Swaminathan teaches the following structure:
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, which does not have a silicon-protected hydroxymethyl group (drawings, figure 8). Although the structure of 26 possesses this silicon-protected hydroxymethyl group, a person of ordinary skill attempting the make the figure 8 structure, would understand to utilize the appropriately protected ethylene diamine reagent. And wherein, as discussed above, X1 can be oxygen, a person of ordinary skill in the art would understand that the appropriate ethylene diamine reagent would naturally lead them to the following structure
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. It is not that the reactions explicitly described for compound 26 leads to the claimed compound, but substitution of the individual components during the synthesis naturally does. It is not that the reaction explicitly describes the production of the claimed compound using compound 23, it is that substitution of compound 23 does. In short, by modifying the following reaction scheme
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with the appropriate ethylene diamine (in view of figure 8) as suggested by Swaminathan, Swaminathan renders obvious the following reaction:
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wherein the silicon protected hydroxy methyl group is omitted. The Examiner notes that the reaction above was shown without appropriate stereochemistry, however, as discussed above in the 103 rejections, Pokorski is relied upon for such a teaching.
On page 5 of the declaration of Appella, the declaration argues the presently claimed invention has an advantageous and superior technical property than previously known molecules attempting to achieve the intended goal, for example molecules disclosed by Swaminathan (section 9). The declaration argues the claimed compounds are able to enter cells, bind to inhibit microRNA-21, the designated microRNA target, and increase the expression of downstream proteins, and entry into the cells do not need the common forms of assistance used with other PNA molecules (Section 9). On pages 5-6 of the declaration of Appella, the declaration argues that the cyclic THF backbone results in improved cell uptake compared to PNAs (section 10). The declaration points to Clausse which confirms this activity (section 10). The declaration points to Nielsen which states it is well known PNAs alone do not enter cells and requires delivery strategies that involve adding positive charges somewhere to the molecule, including adding cell penetrating peptides which can be toxic.
However, as discussed above, Swaminathan teaches tetrahydrofuran backbone oligomers (achiral), and teaches that the therapeutic potential of oligomers is generally enhanced by modifications that increase oligomer uptake by cells or reduce the rate of metabolism by cells or serum, such modifications include (i) reduced oligomer charge, (ii) increased stability toward nuclease activity, and (iii) increased lipophilicity of the oligomer. (pg. 12, lines 21-27). Swaminathan also teaches the oligomers as described exhibit sequence-specific binding to complementary single stranded and duplex target sequences (pg. 12, lines 27-29). Thus it is recognized that oligomer modifications result improved stability and cell uptake. While Swaminathan recognizes delivery of oligomers of the invention into cells can be enhanced by any suitable method including calcium phosphate, DMSO, glycerol or dextran transfection, electroporation or by the use of cationic anionic and/or neutral lipid compositions or liposomes (pg. 35, lines 25-30), it is not taught as a requirement. Furthermore, Clausse which provides evidenced of improved cellular uptake and stability compares the tetrahydrofuran backbone PNA with an acyclic backbone (pg. 10844, figure 1, pg. 10847, figure 3). However Swaminathan teaches tetrahydrofuran backbone oligomers (achiral), and an affidavit or declaration must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness (See MPEP 716.02(e)). Additionally, while Nielsen suggests cell-penetrating peptides are a known approach in the art for increasing PNA bioavailability, Nielsen also recognizes chemical modification as a known approach (pg. 796, last para.), which is supported by the teachings of Swaminathan.
On pages 6-7 of the declaration of Appella, the declaration argues that there is a long-felt need in the industry for such molecules which enter cells much more easily (section 10).
However, as discussed above, Swaminathan teaches tetrahydrofuran backbone oligomers (achiral), and teaches that the therapeutic potential of oligomers is generally enhanced by modifications that increase oligomer uptake by cells or reduce the rate of metabolism by cells or serum (pg. 12, lines 21-27).
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
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/SAMUEL L GALSTER/Examiner, Art Unit 1693
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