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
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 44, 50, 52, 55 and 57-65 are currently pending. Claims 44, 50, 52, 55 and 57-60 have been amended by Applicants’ amendment filed 03-17-2026. Claims 40-43, 45-49, 51, 53, 54, and 56 have been canceled by Applicant’s amendment filed 03-17-2026. Claims 61-65 have been added by Applicants’ amendment filed 03-17-2026.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 44, 50, 52, 55 and 57-65 are under consideration to which the following grounds of rejection are applicable.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 17, 2026 has been considered. An initialed copy of the IDS accompanies this Office Action.
Priority
The present application filed February 6, 2023 is a CON of US Patent Application 16/062,214, filed June 7, 2018, which is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US16/69017, filed December 28, 2016; which claims the benefit of US Provisional Patent Application 62/272,057, filed December 28, 2015.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application 62/272,057, filed December 28, 2015, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 44 does not have support for: wherein said photobase generator is selected from
1,5,7- triazabicyclo[4.4.0]dec-5-enyl-phenylglyoxylate, 1,5,7-triazabicyclo[4.4.0]dec-5-enyl-4-nitro-phenylglyoxylate, 1,5,7-triazabicyclo[4.4.0] dec-5-enyltetraphenylborate, 1,8-Diazabicyclo[5.4.0] undec-7-enyl-1-tetraphenylborate, 1-Phenacy1-(1-azonia-4-azabicyclo[2,2,2]octane)-tetraphenylborate, and 1-Naphthoylmethyl-(1-azonia-4-azabicyclo[2,2,2]octane)-tetraphenylborate. Therefore, the priority date for the presently claimed invention is December 28, 2016, the filing date of US Patent Application WO2017/117292.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claim 44 of the instant application.
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.
Specification Objection
The objection to the disclosure is withdrawn due to Applicants’ amendment of the Specification to identify said amino acid sequences by SEQ ID NOS consistent with the amino acid sequences submitted on February 6, 2023, in the reply filed March 17, 2026.
Maintained Objections/Rejections
Claim Interpretation
The Examiner has determined that the term “PNA or PNA-DNA chimera array produced by the method of claim 44” as recited in claim 58 does not incorporate all of the limitations recited in independent claim 44 into independent claim 58.
Claim Objection
The rejection of claims 44, 50, 52, 55 and 57-60 is maintained, and claims 61-65 are newly objected to because of the following informalities: Claims 44, 50, 52, 55 and 57-65 recite a mixture of pronouns within each claim such as “the” and “said”, such that the Examiner requests that Applicant choose a single pronoun (e.g., the or said) for clarity.
Double Patenting
The rejection of claims 44, 50, 52, 55 and 57 is maintained, and claims 61-65 are newly rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-15 of U.S. Patent No. 10286376;
Claims 1-13 of U.S. Patent No. 12251674; and
Claims 1-10 of U.S. Patent No. 10799845; for the reasons of record.
Response to Arguments
Applicant’s arguments filed March 17, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Applicant requests reconsideration of the rejection in light of the arguments and amendments(Applicant Remarks, pg. 8, second full paragraph).
Regrading (a), Applicant did not specifically indicate how the claims of the copending applications recited supra are patentably distinct from the instant claims as required by 37 CFR 1.111(b). Thus, the claims remain rejected for the reasons already of record.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 44, 50, 52, 55 and 57-60 is maintained, and claims 61-65 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 44, 58, 60 and 65 are indefinite for the recitation of the term “said array” such as recited in claim 44, lines 1 and 11. There is insufficient antecedent basis for the term “said array” in the claim because claim 44, line 1 recites the term “a PNA or PNA-DNA chimera array.” The Examiner suggests that Applicant amend the claim to recite, for example, “said PNA or PNA-DNA chimera array.”
Claim 44 is indefinite for the recitation of the term “the protecting group” such as recited in claim 44, line 8. There is insufficient antecedent basis for the term “the protecting group” in the claim.
Claim 44 is indefinite for the recitation of the term “the amine group” such as recited in claim 44, lines 8-9. There is insufficient antecedent basis for the term “the amine group” in the claim.
Claim 44 is indefinite for the recitation of the terms “said unprotected amine group” and “the unprotected amine group” such as recited in claim 44, lines 10-11 and 14-16. There is insufficient antecedent basis for the terms “said unprotected amine group” and “the unprotected amine group” in the claim.
Claims 44 and 65 are indefinite for the recitation of the term “a plurality of sites on the array” such as recited in claim 44, line 11 because it is unclear whether the “plurality of sites on the array” is related in some way to the “features attached to the surface at positionally-defined locations” and/or to the “area” such as recited in claim 44, lines 2 and 15, whether the “plurality of sites on the array” are structurally different from, and/or are located somewhere different than the features and/or the area of the photoresist exposed to UV light and, thus, the metes and bounds of the claim cannot be determined.
Claims 44, 64 and 65 are indefinite for the recitation of the term “the acetic acid” such as recited in claim 44, line 11. There is insufficient antecedent basis for the term “the acetic acid” in the claim because claim 44, line 10 recites the term “a PNA monomer acetic acid.” The Examiner suggests that Applicant amend the claim to recite, for example, “wherein the PNA monomer acetic acid comprises a substitution.”
Claim 44 is indefinite for the recitation of the term “the area” such as recited in claim 44, line 15. There is insufficient antecedent basis for the term “the area” in the claim.
Claims 44 and 52 are indefinite for the recitation of the terms “step” or “steps” such as recited in claim 44, line 15 because claim 44 does not recite the terms “step” or “steps,” such that it is unclear what is being referred to and, thus, the metes and bounds of the claim cannot be determined.
Claim 52 is indefinite for the recitation of the terms “repeated;” “particular PNA monomer acetic acids;” “in each cycle;” and “specific PNA sequence of a desired length” such as recited in claim 52, lines 2-3 because claim 52 depends from instant claim 44, wherein claim 44 does not recite the any particular PNA monomer acetic acids; a specific PNA sequence of a desired length; and/or that steps (a) to (c) are repeated or cycled and, thus, the metes and bounds of the claim cannot be determined.
Claim 57 is indefinite for the recitation of the terms “each PNA polymer chain” and “PNA-DNA chimeric oligonucleotide polymer chain” such as recited in claim 57, lines 1-2 because claim 57 depends from instant claim 44, wherein the preamble of claim 44 is not accorded any patentable weight (See, In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951)), and the body of instant claim 44 does not recite PNA polymer chains and PNA-DNA chimeric oligonucleotide polymer chains and, thus, the metes and bounds of the claim cannot be determined.
Claim 58 is indefinite for the recitation of the term “produced by the method of claim 44” in claim 58, line 4 because independent claim 58 is a process claim that refers back to independent process claim 44. Moreover, claim 58 uses specific “product-by-process” language, however, instant claim 44 is directed to a method of making an array, such that a product is not produced in claim 44 and, thus, the metes and bounds of the claim cannot be determined.
Claim 58 is indefinite for the recitation of the term “facilitate” such as recited in claim 58, line 4
because the term “facilitate” is a relative term that renders the claim indefinite. The term “facilitate” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of ‘facilitation’ as compared to some other value that qualifies conditions as ‘facilitating hybridization’, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention and, thus, the metes and bounds of the claim cannot be determined.
Claim 58 is indefinite for the recitation of the term “the presence, absence or amount of sample” such as recited in claim 58, lines 6-7. There is insufficient antecedent basis for the term “the presence, absence or amount of sample” in the claim.
Claim 58 is indefinite for the recitation of the term “said positionally defined locations” such as recited in claim 58, lines 7-8 because claims 44 and 58 do not recite the term “positionally defined locations” in the body of either claim, such that it is completely unclear what “positionally defined locations” are being referred to and, thus, the metes and bounds of the claim cannot be determined.
Claim 59 is indefinite for the recitation of the terms “analyzing comprises determining the presence or absence of an SNP” in claim 59, lines 1-2 because claim 59 depends from instant claim 58, wherein claim 58 already recites that ‘analyzing comprises analyzing the signal’, such that “analyzing” cannot comprise something different in claim 59 (e.g., determining the presence or absence of an SNP). Moreover, instant claim 58 recites that the signal indicates the presence, absence or amount of sample hybridized to said array, such that the signal cannot, in a dependent claim, indicate something different (e.g., the presence or absence of an SNP) and, thus, the metes and bounds of the claim cannot be determined.
Claim 60 is indefinite for the recitation of the term “said array comprises PNA-DNA chimeras” such as recited in claim 60, lines 1-2 because claim 60 depends from claims 44, 58 and 59 do not recite the term “PNA-DNA chimeras”, such that it is completely unclear what “PNA-DNA chimeras” are being referred to and, thus, the metes and bounds of the claim cannot be determined.
Claim 63 is indefinite for the recitation of the term “R-thymine-1-acetic acid…R is H or a protecting group” such as recited in claim 63, lines 1-3 because it is unclear where “R” is located within the monomeric structure, such that the identity the functional group being protected is unclear, as well as, the subsequent potential identity of the protecting groups are also unclear and, thus, the metes and bounds of the claim cannot be determined.
Claims 64 and 65 are indefinite for the recitation of the terms “said PNA monomer” or “the PNA monomer” such as recited in claim 64, line 1. There is insufficient antecedent basis for the terms “said PNA monomer” and “the PNA monomer” in the claims because claim 44 recites the term “a PNA monomer acetic acid.”
Claim 64 is indefinite for the recitation of the term “a substituted acetic acid” such as recited in claim 64, line 2 because claim 64 depends from instant claim 44, wherein claim 44 does not recite the presence of a “substituted acetic acid” and, thus, the metes and bounds of the claim cannot be determined.
Claim 64 is indefinite for the recitation of the term “the activated acetic acid” such as recited in claim 64, lines 2-3. There is insufficient antecedent basis for the term “the activated acetic acid” in the claim because claim 64 recites the term “activating a substituted acetic acid.”
Claim 64 is indefinite for the recitation of the term “the unprotected amine groups” such as recited in claim 64, line 3. There is insufficient antecedent basis for the term “the unprotected amine groups” in the claim. Moreover, claim 64 depends from instant claim 44, wherein claim 44 does not recite a plurality of unprotected amine groups, but instead recites the term “the unprotected amine group.”
Claim 64 is indefinite for the recitation of the term “said selectively exposed area” such as recited in claim 64, line 3. There is insufficient antecedent basis for the term “said selectively exposed area” in the claim.
Claim 50, 55, 61 and 62 are indefinite insofar as they ultimately depend from instant claim 44.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 52 and 57 is maintained, and claims 60 and 64 are newly rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 52 recites (in part): “wherein steps (a) to (c) are repeated with particular PNA monomer acetic acids in each cycle to yield a specific PNA sequence of a desired length” in lines 1-3 because claim 52 depends from instant claim 44, wherein claim 44 does not recite steps, repeating reactions or cycles of reactions, the presence of a particular PNA monomer acetic acid, and/or the presence of a specific PNA sequence of a desired length. Thus, claim 52 is an improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 57 recites (in part): “wherein each PNA polymer chain or PNA-DNA chimeric oligonucleotide polymer chain is from 5 to 100 monomers in length” in lines 1-2 because claim 57 depends from instant claim 44, wherein claim 44 does not recite individual PNA polymer chains and/or PNA-DNA chimeric oligonucleotide polymer chains. Thus, claim 57 is an improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 60 recites (in part): “wherein said array comprises PNA-DNA chimeras” in lines 1-2 because claim 60 depends from claims 58 and 59, wherein claims 58 and 59 do not recite the presence or formation of PNA-DNA chimeras. Thus, claim 60 is an improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 64 recites (in part): “wherein said coupling of said PNA monomer comprises: activating a substituted acetic acid by an activation agent, and coupling of the activated acetic acid to the unprotected amine groups at said selectively exposed area, and wherein the substitution of the acetic acid comprises a leaving group” in lines 1-4 because claim 64 depends from instant claim 44, wherein claim 44 does not recite the presence of PNA monomers, activated acetic acid, unprotected amine groups and/or selectively exposed areas. Thus, claim 64 is an improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The rejection of claims 58-60 is maintained under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Egholm et al. (hereinafter “Egholm”) (US Patent No. 6316230, issued November 13, 2001).
Regarding claim 58, Egholm teaches that the PNA-DNA chimera is immobilized to a solid substrate through an ionic attraction, affinity/receptor interaction, or covalent linkage, wherein the solid substrate can be particles, beads, membranes, frits, slides, plates, micromachined chips, alkanethiol-gold layers, non-porous surfaces, or other polynucleotide immobilizing media including polystyrene, controlled-pore-glass, silica gel, silica, polyacrylamide, magnetic beads, polyacrylate, hydroxyethyl methacrylate, polyamide, polyethylene, polyethyleneoxy, and copolymers and grafts of such (interpreted as a PNA-DNA chimera array, claim 58) (col 17, lines 18-27). Egholm teaches primed in situ labeling (PRINS) is a molecular cytogenetic technique that combines the high sensitivity of PCR with the cellular or chromosome localization of fluorescent signals provided by in situ hybridization, such that PRINS can be conducted by annealing unlabeled PNA-DNA chimera primers to complementary target sequences, followed by a DNA polymerase extension in the presence of labelled dNTP, including wherein the labels are fluorescent dyes, so that the extension products can be detected and/or measured by fluorescence detection (Koch, 1991) (interpreted as hybridization of a sample to the array; detecting a signal to determine the presence, absence or amount of sample hybridized; signal intensity; and extension, claim 58) (col 17, lines 8-17). Egholm teaches that a class of labels are electrophoretic mobility modifiers, e.g. polyethyleneoxy (PEO) units, wherein the PEO label can be comprised of charged groups, such as phosphodiester to impart charge and increase electrophoretic mobility (velocity), such that the PEO label can be uncharged and act to retard electrophoretic mobility, wherein such modifiers can serve to influence or normalize the electrophoretic velocity of a set of labelled primer extension products during analysis, e.g. by fluorescent detection, to improve resolution and separation (Grossman, 1995) (interpreting fluorescence detection as analyzing the signal, claim 58) (col 15, lines 15-24). Egholm teaches that "mini-sequencing" is another application involving incorporation of terminating nucleotides in single-base extension assays where PNA-DNA chimera can be useful to determine the identity, presence, or absence of a nucleotide base at a specific position in a nucleic acid target of interest, wherein genotype determination based on identification of different alleles is based on single nucleotide polymorphisms (SNP), wherein SNPs can be detected by ddNTP incorporation from PNA-DNA chimera primers annealed immediately adjacent to the 3’ of the SNP site of the target nucleic acid sequence to be determined, and detection of the extension products by MALDI-TOF mass spectroscopy (FIG 14) (interpreted as a method of analyzing a sample comprising nucleic acids; contacting the array with a sample; conditions that promote hybridization; and analyzing a signal, claim 58) (col 16, lines 58-67; col 17, lines 1-3; and Figure 14). Figure 14 is shown below:
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Regarding claims 59 and 60, Egholm teaches that Figure 14 is a schematic of single nucleotide polymorphism (SNP) detection by one-base PNA-DNA chimera primer extension from wild type (W1) and mutant templates, and MALDI-TOF mass spectral analysis of extension products (interpreted as determining the presence or absence of an SNP in a sample based on a signal; and primer extension, claim 59) (col 7, lines 64-67). Egholm teaches that the SNP can be detected by ddNTP incorporation from PNA-DNA chimera primers annealed immediately adjacent to the 3' of the SNP site of the target nucleic acid sequence to be determined, and detection of the extension products by MALDI-TOF mass spectroscopy (FIG. 14) (interpreted as determining the presence or absence of an SNP in a sample based on a signal; and primer extension after hybridization, claims 59 and 60) (col 16, lines 65-67; col 18, lines 1-3; and Figure 14). Egholm teaches that the invention provides a method of producing a template-dependent, non-radioisotopically labelled chimeric extension products by enzymatically extending a PNA-DNA chimera primer annealed to a template nucleic acid in the presence of a polymerase and a primer extension reagent (FIG. 2) comprising a nucleotide 5'-triphosphate capable of supporting template-dependent extension, wherein the chimera and/or the nucleotide 5'-triphosphate can be labelled with a non-radioisotopic label such that the extension products are non-radioisotopically labelled including wherein the PNA-DNA chimera has the formula: Px-L-Ny 3', where each P is independently a PNA monomer, x is an integer from 5 to 15, L represents a covalent linkage between P and N, each N is independently a nucleotide, y is an integer from 3 to 15, and the 3' terminal N has a 3' hydroxyl group (FIG. 1D) (interpreted as primer extension, claim 60) (col 3, lines 49-65; and Figures 1D and 2).
Egholm meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Response to Arguments
Applicant’s arguments filed March 17, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Applicant amends claims 58-60 to depend from claim 44, which is not rejected under 35 USC 102(a) as being anticipated by Egholm, such that Egholm does not anticipate claims 58-60 as amended (Applicant Remarks, pg. 12, last partial paragraph; and pg. 13, first partial paragraph).
Regrading (a), as an initial matter, instant claim 58 is an independent claim such that it cannot depend from independent claim 44. Thus, the Examiner has determined that the term “PNA or PNA-DNA chimera array produced by the method of claim 44” as recited in claim 58 does not incorporate all of the limitations recited in independent claim 44 into independent claim 58. Regarding Applicant’s argument, Applicant did not specifically indicate how the claims of the copending applications recited supra are patentably distinct from the instant claims as required by 37 CFR 1.111(b). Thus, the claims remain rejected for the reasons already of record.
Claim Rejections - 35 USC § 103
Please Note: the references have been modified slightly in view of Applicant’s amendments and arguments, filed 03-17-2026.
The rejection of claims 44, 50, 52, 55 and 57-60 is maintained, and claims 61-65 are newly rejected under 35 U.S.C. 103 as being unpatentable over Egholm et al. (hereinafter “Egholm”) (US Patent No. 6316230, issued November 13, 2001) in view of Rajasekaran et. al. (hereinafter “Rajasekaran”) (International Application WO2014/078606, published May 22, 2014) as evidenced by ChemPep (ChemPep, 2026, 2); and Wiessler et al. (hereinafter “Wiessler”) (International Journal of Medical Sciences, 2010, 7(4), 213-223).
Regarding claims 44 (in part), Egholm teaches that PNA-DNA chimera are oligomer molecules with discrete PNA and nucleotide moieties, wherein they can be synthesized by covalently linking PNA monomers and nucleotides in virtually any combination or sequence, such that efficient and automated methods have been developed for synthesizing PNA-DNA chimera, which are designed to have desirable properties found in PNA and DNA including superior hybridization properties of PNA and biological functions like DNA (interpreted as PNA-DNA chimera, claims 44 and 58) (col 2, lines 33-41). Egholm teaches that the template nucleic acid or the PNA-DNA chimera can be immobilized on a solid substrate, such that the template or chimera is covalently attached to the solid substate such as via a terminal monomer unit (interpreted as immobilized on a surface, claims 44 and 58) (col 4, lines 66-67; and col 5, lines 1-2). Egholm teaches the simultaneous detection of multiple spectrally-resolvable fluorescent dyes, which are particularly well-suited for detecting, identifying, or determining classes of primer extension products that have been subjected to a separation procedure, such as electrophoresis, or that have been distributed amongst locations in a spatially-addressable hybridization array (interpreted as PNA-DNA chimera array; on a surface; and at positionally defined locations, claims 44 and 58) (col 5, lines 50-57). Egholm teaches that synthesis of the chimera is initiated by detritylation of the 5’ dimethoxytrityl (DMT) group of commercially available, high-cross link, polystyrene beads packed in a synthesis column, wherein 5’ DMT deoxynucleosides are linked through the 3’ hydroxyl to the support through a base-labile succinate/hydroxymethylbenzoic acid linker; and the 5' DMT, 3' cyanoethyl phosphoramidite deoxynucleoside monomers are delivered concurrently with tetrazole activator and coupled to the support-bound 5’ hydroxyl (interpreted as a protected reverse phosphoramidite; and deprotecting via detritylation; the phosphoramidite comprises DMT protecting group; deprotecting; and PNA attached 5’ to the surface, claims 44 and 58) (col 10, lines 32-42). Egholm teaches that the DNA synthesis cycle is repeated until the last deoxynucleoside addition, where a 5'-monomethoxytrityl (MMT) amino nucleoside phosphoramidite is employed to furnish a 5' amino terminus on the support-bound DNA moiety, for coupling to a PNA monomer at the linkage between DNA and PNA in the chimera, wherein the MMT group is favored in the synthesis of PNA-DNA chimera because of its acid-lability, such that the MMT group is efficiently and rapidly removed under mild acidic conditions which do not cause depurination or other damage to the chimera (interpreted as reverse DNA synthesis; adding monomers; deprotecting with MMT; repeating; and inherently comprising a purity, and an average coupling efficiency of a predetermined sequence, claim 44) (col 10, lines 45-55). Egholm teaches that PNA-DNA chimera can be synthesized using the respective conventional methods of synthesis of PNA oligomers, DNA oligonucleotides, and RNA oligonucleotides, wherein chimera can be synthesized at a 2-25 µmole scale on commercially available, automated synthesizers (interpreted as encompassing activating the PNA monomer acetic acid, and reacting with an unprotected amine, claim 44) (col 10, lines 22-26). Egholm teaches that preferred form of the PNA moiety is an uncharged backbone of N-(2-aminoethyl)-glycine, a peptide-like, amide-linked unit (Egholm, 1993; Nielsen, 1991) (Figure 1A) (col 9, lines 62-67; and Figure 1A). Egholm teaches to initiate synthesis of the PNA moiety, the 5' MMT group is removed (e.g., deprotected) with 3% trichloroacetic acid in dichloromethane and the amino group is coupled with a PNA monomer and a coupling reagent such as HBTU or HATU (interpreted as activating and coupling the PNA monomer acetic acid to an unprotected amine; and comprising a leaving group, claims 44 and 64) (col 10, lines 56-64), where it is known that PNA monomers are synthesized by combining an N-(2-aminoethyl)glycine (AEG) backbone with a nucleobase acetic acid, followed by the incorporation of protecting groups to facilitate solid-phase peptide synthesis (SPPS), such that nucleobases are funtionalized to form nucleobase acetic acids, and the AEG backbone is synthesized with a temporary protecting group on the primary amine, such as 9-fluorenylmethoxycarbonyl (Fmoc) or tert-butyloxycarbonyl (Boc) as evidenced by ChemPep (pg. 1, #1); and where it is known that PNA monomers are synthesized by reaction between ethylenediamine 6 and chloride acetic acid-tert-butyl ester 7 as evidenced by Wiessler (pg. 716, Figure 2).
Regarding claim 52, Egholm teaches that the DNA synthesis cycle is repeated until the last deoxynucleoside addition, where a 5'-monomethoxytrityl (MMT) amino nucleoside phosphor-amidite is employed to furnish a 5' amino terminus on the support-bound DNA moiety, for coupling to a PNA monomer at the linkage between DNA and PNA in the chimera (interpreted as activating the reverse phosphoramidite; coupling the first DNA monomer; coupling the second DNA monomer; repeating; and unprotected amino group in the PNA polymer, claim 46) (col 10, lines 45-51).
Regarding claim 57, Egholm teaches that PNA-DNA chimera are linear oligomers comprised of: (1) a contiguous moiety of PNA monomer units and (2) a contiguous moiety of nucleotides, wherein the two moieties are covalently linked together, such that the nucleotide moiety of the chimera can be 2'-deoxy-nucleotides, ribonucleotides, or a mixture thereof; and the nucleotide moiety of the chimera has a 3' hydroxyl terminus, wherein the preferred length of the PNA moiety is from 5 to 15 PNA monomer units, reflecting optimum enzymatic activity, hybridization specificity and affinity, economy of synthesis reagents, and ease of chimera synthesis and purification (interpreted as encompassing a PNA chain of about 3 bases, claim 57) (col 9, lines 46-57). Egholm teaches that primer extension was reported using a mixture of PNA-DNA chimera consisting of 19 PNA monomer units with three (FIG 1D) and four 2’-deoxynucleotides, labelled once and twice, respectively (interpreting a PNA chain comprising 15 bases and a PNA chain extension of 19 bases to be at least 30 bases; and encompassing 5 to 100 bases, claim 57) (col 2, lines 54-56; and Figure 1D).
Regarding claim 58, Egholm teaches that the PNA-DNA chimera is immobilized to a solid substrate through an ionic attraction, affinity/receptor interaction, or covalent linkage, wherein the solid substrate can be particles, beads, membranes, frits, slides, plates, micromachined chips, alkanethiol-gold layers, non-porous surfaces, or other polynucleotide immobilizing media including polystyrene, controlled-pore-glass, silica gel, silica, polyacrylamide, magnetic beads, polyacrylate, hydroxyethyl methacrylate, polyamide, polyethylene, polyethyleneoxy, and copolymers and grafts of such (interpreted as a PNA-DNA chimera array, claim 58) (col 17, lines 18-27). Egholm teaches primed in situ labeling (PRINS) is a molecular cytogenetic technique that combines the high sensitivity of PCR with the cellular or chromosome localization of fluorescent signals provided by in situ hybridization, such that PRINS can be conducted by annealing unlabeled PNA-DNA chimera primers to complementary target sequences, followed by a DNA polymerase extension in the presence of labelled dNTP, including wherein the labels are fluorescent dyes, so that the extension products can be detected and/or measured by fluorescence detection (Koch, 1991) (interpreted as hybridization of a sample to the array; detecting a signal to determine the presence, absence or amount of sample hybridized; signal intensity; and extension, claim 58) (col 17, lines 8-17). Egholm teaches that a class of labels are electrophoretic mobility modifiers, e.g. polyethyleneoxy (PEO) units, wherein the PEO label can be comprised of charged groups, such as phosphodiester to impart charge and increase electrophoretic mobility (velocity), such that the PEO label can be uncharged and act to retard electrophoretic mobility, wherein such modifiers can serve to influence or normalize the electrophoretic velocity of a set of labelled primer extension products during analysis, e.g. by fluorescent detection, to improve resolution and separation (Grossman, 1995) (interpreting fluorescence detection as analyzing the signal, claim 58) (col 15, lines 15-24). Egholm teaches that "mini-sequencing" is another application involving incorporation of terminating nucleotides in single-base extension assays where PNA-DNA chimera can be useful to determine the identity, presence, or absence of a nucleotide base at a specific position in a nucleic acid target of interest, wherein genotype determination based on identification of different alleles is based on single nucleotide polymorphisms (SNP), wherein SNPs can be detected by ddNTP incorporation from PNA-DNA chimera primers annealed immediately adjacent to the 3’ of the SNP site of the target nucleic acid sequence to be determined, and detection of the extension products by MALDI-TOF mass spectroscopy (FIG 14) (interpreted as a method of analyzing a sample comprising nucleic acids; contacting the array with a sample; conditions that promote hybridization; and analyzing a signal, claim 58) (col 16, lines 58-67; col 17, lines 1-3; and Figure 14). Figure 14 is shown below:
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Regarding claims 59 and 60, Egholm teaches that Figure 14 is a schematic of single nucleotide polymorphism (SNP) detection by one-base PNA-DNA chimera primer extension from wild type (W1) and mutant templates, and MALDI-TOF mass spectral analysis of extension products (interpreted as determining the presence or absence of an SNP in a sample based on a signal, claim 59) (col 7, lines 64-67). Egholm teaches that the SNP can be detected by ddNTP incorporation from PNA-DNA chimera primers annealed immediately adjacent to the 3' of the SNP site of the target nucleic acid sequence to be determined, and detection of the extension products by MALDI-TOF mass spectroscopy (FIG. 14) (interpreted as determining the presence or absence of an SNP in a sample based on a signal; and primer extension after hybridization, claims 59 and 60) (col 16, lines 65-67; col 18, lines 1-3; and Figure 14). Egholm teaches that the invention provides a method of producing a template-dependent, non-radioisotopically labelled chimeric extension products by enzymatically extending a PNA-DNA chimera primer annealed to a template nucleic acid in the presence of a polymerase and a primer extension reagent (FIG. 2) comprising a nucleotide 5'-triphosphate capable of supporting template-dependent extension, wherein the chimera and/or the nucleotide 5'-triphosphate can be labelled with a non-radioisotopic label such that the extension products are non-radioisotopically labelled including wherein the PNA-DNA chimera has the formula: Px-L-Ny 3', where each P is independently a PNA monomer, x is an integer from 5 to 15, L represents a covalent linkage between P and N, each N is independently a nucleotide, y is an integer from 3 to 15, and the 3' terminal N has a 3' hydroxyl group (FIG. 1D) (interpreting PNA monomers to comprise substituted acetic acid; comprising a protecting group; and primer extension, claims 44 and 60) (col 3, lines 49-65; and Figures 1D and 2),
Egholm does not specifically exemplify generating a pattern using a photomask; uv light; photoresist; a photobase generator; and the photobase generators recited in claim 44 (claims 44, in part); where the photobase generator is 1,3-Bis[(2-nitrobenzyl)oxycarbonyl-4-piperidyl]propane (claim 50); and coupling efficiency (claims 55, 61 and 62); and wherein the PNA monomer comprising a halo leaving group and reacting with a diamino-alkane (claim 65).
Regarding claims 44 (in part) and 50, Rajasekaran teaches that the spatial orientation of the occurrence of these chemical reactions is thus defined according to a pattern of electromagnetic radiation the solution or surface comprising photoactive compounds is exposed to, such that this pattern can be defined, e.g., by a photomask or reticle (interpreted as forming a pattern using a photomask and uv light, claims 44 and 58) (paragraph [0055]). Rajasekaran teaches coupling molecules include, but are not limited to, boc-Gly-COOH, Fmoc-Trp-COOH; as well as, monomer molecules and combinations thereof that can form polymers upon coupling, e.g., nucleotides, sugars and the like (interpreted as PNA monomer acetic acids, claim 44) (paragraph [0068]). Rajasekaran teaches the use of linking molecules including diamines, diacids, amino acids, and combinations thereof, such as ethylene diamine and diamino propane (paragraph [00118]). Rajasekaran teaches formulations, substrates, and arrays including methods for manufacturing and using the formulations, substrates, and arrays, wherein an array that is manufactured using a photoactive coupling formulation such as a carboxylic acid activating compound, and a substrate comprising carboxylic acid groups, wherein the photoactive coupling formulation comprises a photoactive compound, a coupling molecule, a polymer, and a solvent; such that attaching the coupling molecule to the substrate comprises selectively exposing either the photoactive compound or the photoactive carboxylic acid activating compound to light, wherein the photoactive compound is about 0.5-5% by weight of the total formulation; and that examples of coupling molecules include, but are not limited, to amino acids, peptides, proteins, DNA binding sequences, antibodies, oligonucleotides, nucleic acids, peptide nucleic acids ("PNA"), deoxyribonucleic acids (DNA), ribonucleic acids (RNA), peptide mimetics, nucleotide mimetics, chelates, biomarkers and the like (paragraphs [0006]-[0007]). Rajasekaran teaches that the method of preparing a substrate surface can include obtaining a surface comprising silicon dioxide and contacting the surface with a photoactive coupling formulation comprising a photoactive compound, a coupling molecule, a coupling reagent, a polymer, and a solvent; and applying ultraviolet light to positionally-defined locations located on the top of the surface and in contact with the photoactive formulation (interpreted as generating a pattern on positionally-defined locations using a photomask, uv light; and a photoactive compound, claim 44) (paragraph [00178]). Rajasekaran teaches that the arrays disclosed herein can be synthesized in situ on a surface, e.g., a substrate disclosed herein including by using photolithography, wherein the substrate is contacted with a photoactive coupling solution, such that masks can be used to control radiation or light exposure to specific locations on a surface provided with free linker molecules or free coupling molecules having protecting groups, wherein coupling molecules include any natural or artificially synthesized amino acid with its amino group protected with a fluorenylmethyloxycarbonyl (Fmoc) group or a t-butoxy-carbonyl (t-Boc or Boc) group; and that in the exposed locations, the protecting groups are removed, resulting in one or more newly exposed reactive moieties on the coupling molecule or linker molecule, wherein the desired linker or coupling molecule is then coupled to the unprotected attached molecules, e.g., at the carboxylic acid group, such that the process can be repeated to synthesize a large number of features in specific or positionally-defined locations on a surface (interpreted as generating a pattern using a photomask, uv light; and a photoactive compound, claim 44) (paragraphs [0056]; and [00178]). Rajasekaran teaches that photoactive compounds comprise a photobase generator having the structure of formula (II) below:
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wherein the photobase generator is 1,3-Bis[(2-nitrobenzyl)oxycarbonyl-4-piperidyl]propane or 1,3- Bis[1-(9-fluorenylmethoxycarbonyl)-4-piperidyl]propane, wherein the photobase generator is a carbamate, o-acyloxime, ammonium salt, amineimide, a-aminoketone, amidine precursor, or aromatic urea (interpreted as a photobase generator including as recited in claim 44 including 1,3-bis[(2-nitrobenzyl)oxycarbonyl-4-piperidyl]propane, claims 44 and 50) (paragraphs [0010]-[0011]). Rajasekaran teaches that the features comprise a plurality of distinct, nested, overlapping peptide chains comprising subsequences derived from a source protein having a known sequence, wherein each peptide chain in the plurality is at least 5 amino acids in length and/or each peptide chain in the plurality is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids in length (interpreted as encompassing at least 30 PNA monomers; and 5 to 100 monomers in length, claims 56 and 57) (paragraph [0025]).
Regarding claims 49 and 50, Rajasekaran teaches that photoactive compounds comprise a photobase generator having the structure of formula (II) below:
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wherein the photobase generator is 1,3-Bis-[(2-nitrobenzyl)oxycarbonyl-4-piperidyl]propane or 1,3- Bis[1-(9-fluorenylmethoxycarbonyl)-4-piperidyl]propane, wherein the photobase generator is a carbamate, o-acyloxime, ammonium salt, amineimide, a-aminoketone, amidine precursor, or aromatic urea (interpreted as a photobase generator including as recited in claim 49, claims 49 and 50) (paragraphs [0010]-[0011]).
Regarding claims 55, 61 and 62, Rajasekaran teaches that the term “coupling efficiency" refers to the probability of successful addition of a monomer to a reaction site (e.g., at the end of a polymer) available for binding to the monomer, such as during the growth of a peptide chain in the N to C orientation, a polypeptide having a free carboxyl group would bind to an amino acid having a free amine group under appropriate conditions, wherein the coupling efficiency gives the probability of the addition of a free amino acid to the free carboxyl group under certain conditions, and it can be determined in bulk, e.g., by monitoring single monomer additions to several unique reaction sites simultaneously (interpreted as a coupling efficiency of at least 98.5%, claim 55) (paragraph [0058]). Rajasekaran teaches that within an individual feature, the fraction of peptide chains within said collection having the intended length is characterized by an average coupling efficiency for each coupling step of greater than 98% including 100% (interpreted as a predetermined length; and characterized by a coupling efficiency of at least 98.5%, claims 55, 61 and 62) (paragraphs [00169]-[00170]).
Although the combined references do not specifically exemplify wherein the PNA monomer comprising a halo leaving group, Egholm does teach the synthesis of PNA-DNA probes using conventional techniques; while Rajasekaran does teach the production of PNA probe arrays and the use of diamines such as ethylene diamine and diamino propane as linkers, where it was known in the art that conventional methods include reacting ethylenediamine and chloride acetic acid-tert-butyl ester as evidenced by Wiessler; and where it is known that PNA monomers are synthesized by combining an N-(2-aminoethyl)-glycine (AEG) backbone with a nucleobase acetic acid, followed by the incorporation of protecting groups, wherein nucleobases are funtionalized to form nucleobase acetic acids, and the AEG backbone is synthesized with a temporary protecting group on the primary amine as evidenced by ChemPep, such that one of ordinary skill in the art would clearly recognize the well-known, conventional, and routine organic synthesis processes used to synthesize PNA-DNA chimeras.
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 using photolithographic synthesis and photoactive coupling formulations for the attachment of polymer or biomolecules to a substrate as exemplified by Rajasekaran, it would have been prima facia obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of producing PNA-DNA chimera arrays including PNA-DNA chimeras comprising fluorescent dyes or other labels as disclosed by Egholm to include the photolithographic synthesis methods and photobase generators as taught by Rajasekaran with a reasonable expectation of success in the high efficiency one-step coupling of biomolecules including PNAs to a substrate; and/or in producing PNA-DNA chimera arrays that can be used in DNA sequencing, DNA fragment analysis, reverse transcription, mini-sequencing, chromosome labelling, amplification, and SNP detection.
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.
Response to Arguments
Applicant’s arguments filed March 17, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Applicant submits that Egholm does not teach or suggest activating the PNA monomer acetic acid for coupling a PNA monomer to a unprotected amine group (Applicant Remarks, pg. 14, first full paragraph); (b) Rajasekaran does not teach a PNA monomer acetic acid, such that a prima facie case of obviousness would not have been established (Applicant Remarks, pg. 14, second and third full paragraphs); and (c) Applicant submits that the term "peptide nucleic acid" appears only twice in the description of Rajasekaran, in paragraphs [0007] and [00065]. These instances are as members of long lists of possible coupling molecules or probe molecules. The term "peptide nucleic acid" also appears, only once, in the claims in another long list of possible "features" in claim 209 of Rajasekaran (Applicant Remarks, pg. 14, last full paragraph).
Regrading (a) and (b), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). Additionally, MPEP 2112.01(I) states that:
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Applicant’s assertion that the combined references of Egholm and Rajasekaran do not teach activating the PNA monomer acetic acid for coupling a PNA monomer to a unprotected amine group, is not found persuasive. As an initial matter, the Examiner notes that a PNA monomer comprises a “PNA monomer acetic acid” such as shown in the structure of 2-aminoethylglycine below:
H2N-(CH2)2-NH-CH2-CO2H
and that activating and coupling a “PNA monomer acetic acid” to an unprotected amine is a well-known, conventional, and routine method of producing PNA monomers and/or PNA-DNA chimeras. To that end -
Egholm teaches:
PNA-DNA chimera can be synthesized using the respective conventional methods of synthesis of PNA oligomers, DNA oligonucleotides, and RNA oligonucleotides including on commercially available, automated synthesizers (interpreted as encompassing activating the PNA monomer acetic acid, and reacting with an unprotected amine, claim 44) (col 10, lines 22-26).
where it is known that PNA monomers are synthesized by combining an N-(2-aminoethyl)-glycine (AEG) backbone with a nucleobase acetic acid, followed by the incorporation of protecting groups to facilitate solid-phase peptide synthesis (SPPS), such that nucleobases are funtionalized to form nucleobase acetic acids, and the AEG backbone is synthesized with a temporary protecting group on the primary amine as evidenced by ChemPep (pg. 1, #1); and
where it is known that PNA monomers are synthesized by reaction between ethylenediamine and chloride acetic acid-tert-butyl ester as evidenced by Wiessler (pg. 716, Figure 2).
To initiate synthesis of the PNA moiety, the 5' MMT group is removed (e.g., deprotected) with and the amino group is coupled using HBTU or HATU with a PNA monomer and a coupling reagent (interpreted as deprotecting, activating, and coupling the PNA monomer acetic acid to an unprotected amine, claim 44) (col 10, lines 56-64).
The PNA moiety is an uncharged backbone of N-(2-aminoethyl)-glycine, a peptide-like, amide-linked unit (Egholm, 1993; Nielsen, 1991) (Figure 1A) (interpreted as the AEG backbone for activating the PNA monomer acetic acid, and reacting with an unprotected amine, claim 44) (col 9, lines 62-67; and Figure 1A).
Rajasekaran teaches:
Manufacturing probe arrays including peptide, oligonucleotide, DNA, RNA, peptide nucleic acid (PNA), and the like (paragraphs [00143]).
Coupling molecules include, but are not limited to, boc-Gly-COOH, Fmoc-Trp-COOH; as well as, monomer molecules and combinations thereof that can form polymers upon coupling, e.g., nucleotides, sugars and the like (interpreted as PNA monomer acetic acids) (paragraph [0068]).
The combined references teach all of the limitations of the claims. Thus, the claims remain rejected.
Regarding (c), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. Additionally, MPEP 2123(I) states:
"The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. See In re Heck, 699 F.2d 1331, 1332-33,216 USPQ 1038, 1039 (Fed. Cir. 1983); In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275,277 (CCPA 1968); Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); and Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (underline added).
Egholm is directed to PNA-DNA chimera immobilized on a solid substrate; while Rajasekaran is directed to methods of manufacturing arrays including arrays of peptides, oligomers, PNAs, DNAs, RNAs, peptide mimetics, and mixtures thereof. Regarding Applicants’ assertion that Rajasekaran teaches a multiplicity of probe alternatives, the Examiner notes that there might be hundreds or thousands alternative array probes known in the field, but if they were all well-known as of the filing date, they were all equally obvious. The fact that the field of art has become more saturated and well-characterized with known probes for use in microarray systems does not render any given optimization within that field less obvious. The combined references teach all of the limitations of the claims. Thus, the claims remain rejected.
Conclusion
Claims 44, 50, 52, 55 and 57-65 remain rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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