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 .
Claims Status
Claims 115-137 are pending and currently under examination
Priority
This application is a continuation application of U.S. Patent Application No. 17/484.674, filed September 24, 2021, which is a continuation application of U.S. Patent Application No. 15/930,488, filed May 13, 2020, now U.S. Patent No. 11,180,800, issued on November 23, 2021, which is a divisional of U.S. Patent Application No. 15/952,203, filed April 12, 2018, now U.S. Patent No. 10,697,008, issued on June 30, 2020, which claims the benefit of U.S. Provisional Application No. 62/484,856, filed April 12, 2017. The priority date of claim set filed on May 24, 2024, is determined to be April 12, 2017.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 115-137 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 115 is indefinite over the limitation “iii) a cell-free DNA; and iv) a free RNA”. It is unclear if the “free RNA” is also “cell-free”. Claims 116-136 depend on claim 115.
Claim 137 is indefinite over the limitation “iii) a cell-free DNA; and iv) a free RNA”. It is unclear if the “free RNA” is also “cell-free”. Furthermore, it is unclear if the DNA and RNA provided in the kit is considered the sample from a subject or control or whether the DNA or RNA provided in the kit are related to short complementary DNA or RNA fragments such as primers.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 131 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, 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. Regarding claim 131, the limitation “wherein the same sample from the same subject” is not properly depend from claim 129. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 115-137 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards a natural phenomenon of cell free DNA and free RNA and cell free DNA and free RNA derived from a pathogen (virus, a bacterium, a fungus, a pararsite, or any combinations thereof and a routine and conventional reaction mixture/kit, without significantly more. The claim(s) recite(s) natural phenomena and routine and conventional mixture/kit. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 115 is directed towards: A reaction mixture comprising:(i) a DNA-dependent polymerase; (ii) an RNA-selective polymerase (iii) a cell-free DNA, and (iv) a free RNA.
The cell free DNA and free RNA are a natural phenomenon.
“A reaction mixture comprising: i) a DNA-dependent polymerase; ii) an RNA-selective polymerase; iii) a cell-free DNA; and iv) a free RNA.” is considered a routine and conventional reaction mixture.
The instant claim 132 is directed towards: The reaction mixture of claim 115, wherein the cfDNA and free RNA comprise cfDNA, free RNA, or a combination thereof, are derived from a pathogen.
The cell free DNA and free RNA derived from a pathogen is a natural phenomenon.
The instant claim 133 is directed towards: The reaction mixture of claim 132, wherein the pathogen comprises a virus, a bacterium, a fungus, a parasite, or any combination thereof.
The cell free DNA and free RNA derived from a pathogen comprised of a virus, a bacterium, a fungus, a parasite, or any combination thereof is a natural phenomenon.
Dependent claims 116-136 depend on claim 115 and set forth further limitations about DNA-dependent polymerase, RNA- selective polymerase, addition of non-templated bases, nucleic acid forms, cfDNA and free RNA source, reaction vessel, and addition of ligase.
The instant claim 137 is directed towards: A kit comprising: i) a DNA-dependent polymerase; ii) an RNA-selective polymerase; iii) a cell-free DNA; and iv) a free RNA.
The cell free DNA and free RNA are a natural phenomenon.
“A kit comprising: i) a DNA-dependent polymerase; ii) an RNA-selective polymerase; iii) a cell-free DNA; and iv) a free RNA.” is considered a routine and conventional kit.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a composition.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, natural phenomena.
With regards to claim 115: A reaction mixture comprising:(i) a DNA-dependent polymerase; (ii) an RNA-selective polymerase (iii) a cell-free DNA, and (iv) a free RNA.
The cell free DNA and free RNA are a natural phenomenon.
With regards to claim 132: The reaction mixture of claim 115, wherein the cfDNA and free RNA comprise cfDNA, free RNA, or a combination thereof, are derived from a pathogen.
The cell free DNA and free RNA derived from a pathogen is a natural phenomenon.
With regards to claim 133: The reaction mixture of claim 132, wherein the pathogen comprises a virus, a bacterium, a fungus, a parasite, or any combination thereof.
The cell free DNA and free RNA derived from a pathogen comprised of a virus, a bacterium, a fungus, a parasite, or any combination thereof is a natural phenomenon.
With regards to claim 137: A kit comprising: i) a DNA-dependent polymerase; ii) an RNA-selective polymerase; iii) a cell-free DNA; and iv) a free RNA.
The cell free DNA and free RNA are a natural phenomenon.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claims 115 and 137, the claims require the routine and conventional reaction mixture/kit of DNA-dependent polymerase, RNA-selective polymerase, and cell-free DNA and free RNA similar to that of Makarov et al. (“Makarov”; Patent App. Pub. WO 2013138536 A1, Sept. 19, 2013).
Makarov discloses “The present invention is directed to methods and compositions for adding tails of specific lengths to a substrate polynucleotide. The invention also contemplates methods and compositions for immobilization of tailed substrates to a solid support. The disclosure contemplates that the attenuator molecule is any biomolecule that associates with a tail sequence added to a substrate polynucleotide and controls the addition of a tail sequence to the 3' end of the substrate polynucleotide. The sequence that is added to the substrate polynucleotide is referred to herein as a tail sequence, or simply a tail, and the process of adding a nucleotide to a substrate polynucleotide is referred to herein as tailing.” (Abstract).Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require further limitations about DNA-dependent polymerase, RNA- selective polymerase, addition of non-templated bases, nucleic acid forms, cfDNA and free RNA source, reaction vessel, and addition of ligase which are all routine and conventional based on Makarov et al. (“Makarov”; Patent App. Pub. WO 2013138536 A1, Sept. 19, 2013).
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.
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 115-137 are rejected under 35 U.S.C. 103 as being unpatentable over Makarov et al. (“Makarov”; Patent App. Pub. WO 2013138536 A1, Sept. 19, 2013).
Makarov discloses “The present invention is directed to methods and compositions for adding tails of specific lengths to a substrate polynucleotide. The invention also contemplates methods and compositions for immobilization of tailed substrates to a solid support. The disclosure contemplates that the attenuator molecule is any biomolecule that associates with a tail sequence added to a substrate polynucleotide and controls the addition of a tail sequence to the 3' end of the substrate polynucleotide. The sequence that is added to the substrate polynucleotide is referred to herein as a tail sequence, or simply a tail, and the process of adding a nucleotide to a substrate polynucleotide is referred to herein as tailing.” (Abstract).
Regarding claim 115, Makarov teaches a reaction mixture wherein “a composition comprising a nucleic acid polymerase” (Para. 4). Makarov teaches a reaction mixture wherein “In some embodiments, the nucleic acid polymerase is a template-independent polymerase. In one aspect, the nucleic acid polymerase is a DNA polymerase, and in a further aspect the DNA polymerase is terminal deoxynucleotidyl transferase (TdT). In related embodiments, the nucleic acid polymerase is a RNA polymerase, which in various aspects is selected from the group consisting of poly(A) polymerase, RNA-specific nucleotidyl transferase and poly(U) polymerase.” (Para. 6). Makarov teaches a reaction mixture wherein “In some aspects, more than one type of substrate polynucleotide is added to a single reaction vessel. … In further aspects, at least 2 … types of substrate polynucleotides … are added to a single reaction vessel. …multiplexing as well as controlled DNA and RNA tailing-ligation reactions by template independent polymerases such as deoxynucleotidyl transferase (TdT), poly(A) polymerase or poly(U) polymerase.” (Para.184). Thus, Makarov teaches a reaction mixture comprising:(i) a DNA-dependent polymerase; (ii) an RNA-selective polymerase (iii) a cell-free DNA, and (iv) a free RNA.
The teachings of Markov et al. are documented above in the rejection of claim 115 under 35 U.S.C. 103. Claims 116, 117, 118, 119, 123, 124, 128, 129, 132, 134, 136 depend on claim 115. Claim 122 depends on claim 121. Claims 120 and 121 depend on claim 119, which depends on claim 115. Claim 127 depends on claim 125. Claims 125 and 126 depend on claim 124, which depends on claim 115. Claim 130 depends on claim 128, which depends on claim 115. Claim 131 depends on claim 129, which depends on claim 115. Claim 133 depends on claim 132, which depends on claim 115. Claim 131 depends on claim 129, which depends on claim 115. Claim 135 depends on claim 134, which depends on claim 115. Claim 137 is independent of claim 115.
Regarding claims 116, Makarov teaches a reaction mixture wherein “Taq DNA Polymerase… Bst DNA Polymerase, Therminator™ DNA Polymerase … VentR® (exo-) DNA Polymerase” (Para. 115). Thus, Makarov teaches a reaction mixture wherein the DNA-dependent polymerase is selected from a member of the group consisting of: an A- family DNA polymerase, a B-family DNA polymerase, a KOD XL, KOD (exo-), a Bst 2.0, a (New) The rminator, a Deep Vent (exo-), a Pfu DNA polymerase, a Taq, and any combination thereof.
Regarding claim 117, Makarov teaches a reaction mixture wherein “Reverse Transcriptases and RNA Polymerases, AMV Reverse Transcriptase, M-MuLV Reverse Transcriptase, phi6 RNA Polymerase (RdRP)” (Para. 115). Thus, Makarov teaches a reaction mixture wherein the RNA-selective polymerase comprises a reverse transcriptase enzyme (RT), an RNA-dependent RNA polymerase, or a combination thereof.
Regarding claim 118, Makarov teaches a reaction mixture wherein “nucleic acid polymerase is a template-independent polymerase. In one aspect, the nucleic acid polymerase is a DNA polymerase” (Para. 6) and “reactions by template independent polymerases” (Para. 184). Thus, Makarov teaches a reaction mixture wherein the DNA-dependent polymerase has non- templated activity.
Regarding claim 119, Makarov teaches a reaction mixture wherein “the DNA polymerase is terminal deoxynucleotidyl transferase (TdT)” (Para. 6). Makarov teaches a reaction mixture “extending a DNA substrate polynucleotide is provided comprising mixing the DNA substrate polynucleotide with TdT enzyme” (Para. 33).TdT reads on “the DNA-dependent polymerase is capable of an addition of a non-templated base to an end of a nascent growing strand of a duplex”. Thus, Makarov teaches a reaction mixture wherein the DNA-dependent polymerase is capable of an addition of a non-templated base to an end of a nascent growing strand of a duplex.
Regarding claim 120, Makarov teaches a reaction mixture wherein “the polymerase enzyme adds a limited number of bases to the 3' end of DNA substrates” (Para. 57). Thus, Makarov teaches a reaction mixture wherein the addition of the non-templated base to the end of the nascent growing strand of the duplex occurs at a 3' end.
Regarding claim 121, Makarov teaches a reaction mixture wherein “ number of bases added by the polymerase to the 3' end of a DNA substrate is 1, … or more dA, dT or dG nucleotides.” (Para. 62). “bases added by the polymerase to the 3' end of a DNA substrate is 1, … or more dA, dT or dG nucleotides” reads on the non-templated base is N1, wherein N1 is a different nucleic acid base that identifies a first nucleic acid form. “different nucleic acid base that identifies a first nucleic acid form” reads on any nucleic acid base. Thus, Makarov teaches a reaction mixture wherein the non-templated base is N1, wherein N1 is a different nucleic acid base that identifies a first nucleic acid form.
Regarding claim 122, Makarov teaches a reaction mixture wherein “A poly(dA) or poly(A) stretch is then added to the polynucleotide via a template-independent polymerase, and the presence of a DNA polymerase will allow for extension across the DNA or RNA molecule, thereby creating a double stranded product.” (Para. 215; Figure 9B). Thus, Makarov teaches a reaction mixture wherein the first nucleic acid form comprises DNA, wherein the DNA is single-stranded, double-stranded, or a combination thereof.
Regarding claim 123, Makarov teaches a reaction mixture wherein “nucleic acid polymerase is a RNA polymerase, and in these aspects the RNA polymerase is selected from the group consisting of poly(A) polymerase and poly(U) polymerase. In one specific aspect the RNA polymerase is RNA-specific ribonucleotidyl transferase. These polymerases all represent a family a template-independent polymerases.” (Para. 113). Thus, Makarov teaches a reaction mixture wherein the RNA-selective polymerase has non- templated activity.
Regarding claim 124 and 126, Makarov teaches a reaction mixture wherein “a substrate RNA polynucleotide comprising mixing the substrate RNA polynucleotide with an RNA polymerase” (Para. 35). “different nucleic acid base that identifies a second nucleic acid form” reads on any nucleic acid base. Thus, Makarov teaches a reaction mixture wherein the RNA-selective polymerase is capable of an addition of a non-templated base to an end of a nascent growing strand of a duplex; and wherein the non-templated base is N2, wherein N2 is a different nucleic acid base that identifies a second nucleic acid form.
Regarding claims 125 and 127, Makarov teaches a reaction mixture wherein “Part B of Figure 9 depicts a limited tailing-polymerase-extension reaction. In such a reaction, DNA or RNA is incubated with a template-independent polymerase… A poly(dA) or poly(A) stretch is then added to the polynucleotide via a template-independent polymerase, and the presence of a DNA polymerase will allow for extension across the DNA or RNA molecule, thereby creating a double stranded product.” (Para. 215; Figure 9B). Thus, Makarov teaches a reaction mixture wherein the addition of the non-templated base to the end of the nascent growing strand of the duplex occurs at a 3' end; and wherein the second nucleic acid form comprises RNA, wherein the RNA is single-stranded, double-stranded, or a combination thereof.
Regarding claim 128, Makarov teaches a reaction mixture wherein “The substrate polynucleotide is, in various embodiments, DNA, RNA, or a combination thereof. The substrate polynucleotide to which the tail is added is either single stranded or double stranded” (Para. 142). Thus, Makarov teaches a reaction mixture wherein the cfDNA and the free RNA are single- stranded, double-stranded, or a combination thereof.
Regarding claims 129-131, Makarov teaches a reaction mixture wherein “It is contemplated that substrate polynucleotides are obtained from naturally occurring sources … The naturally occurring sources are RNA and/or genomic DNA from a prokaryote or a eukaryote. For example and without limitation, the source can be a human, mouse, virus, plant or bacteria.” (Para.143). “RNA and/or genomic DNA from a prokaryote or a eukaryote” reads on cell-free DNA (cfDNA) and the free RNA are derived from a sample from a subject or a same sample from a same subject, or a same sample from a same subject comprises a low-quality sample. Thus, Makarov teaches a reaction mixture wherein the cell-free DNA (cfDNA) and the free RNA are derived from a sample from a subject; wherein the cell-free DNA (cfDNA) and the free RNA are derived from a sample from a same subject; and wherein the same sample from the same subject comprises a low-quality sample.
Regarding claims 132-133, Makarov teaches a reaction mixture wherein “It is contemplated that substrate polynucleotides are obtained from naturally occurring sources or they can be synthetic. The naturally occurring sources are RNA and/or genomic DNA from a prokaryote or a eukaryote. For example and without limitation, the source can be a human, mouse, virus, plant or bacteria.” (Para. 143). Thus, Makarov teaches a reaction mixture wherein the cfDNA and free RNA comprise cfDNA, free RNA, or a combination thereof, are derived from a pathogen; and wherein the pathogen comprises a virus, a bacterium, a fungus, a parasite, or any combination thereof.
Regarding claim 134, Makarov teaches a reaction mixture wherein “Suitable reaction vessels are known to those of skill in the art and include, without limitation, a microcentrifuge tube or a microtiter plate.” (Para. 183). Thus, Makarov teaches a reaction mixture wherein the reaction mixture is comprised in a container or a tube.
Regarding claim 135, Makarov teaches a reaction mixture wherein “more than one type of substrate polynucleotide is added to a single reaction vessel.” (Para. 184). Thus, Makarov teaches a reaction mixture wherein the container or the tube comprise a single PCR tube or a single reaction tube.
Regarding claim 136, Makarov teaches a reaction mixture wherein “a composition of the disclosure comprises a ligase enzyme” (Para. 19) and “the ligase is a DNA ligase or a RNA ligase” (Para. 27). Thus, Makarov teaches a reaction mixture further comprising a ligase, wherein the ligase comprises a DNA ligase, an RNA ligase, or a combination thereof.
Regarding claim 137, Makarov teaches a kit comprising “reagents for single reaction tailing-ligation-immobilization both for DNA and RNA substrates” (Para. 201). “DNA and RNA substrates” reads on cell-free DNA and free RNA. Thus, Makarov teaches a kit comprising: i) a DNA-dependent polymerase; ii) an RNA-selective polymerase; iii) a cell-free DNA; and iv) a free RNA.
Therefore, the invention as recited in claims 115-137 is prima facie obvious over the prior art Makarov et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to provide a reaction mixture and/or kit according to the limitations of the instant application claims 115-137 based on Makarov et al. (Patent App. Pub. No. WO 2013138536 A1).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Turchinovich et al. (“Turchinovich”; Patent App. Pub. WO 2015173402 A1, Nov. 11, 2015) - Claim 115 and 137 (Pg. 41 (ln 25-30) Claim 23
No claims are in condition for allowance.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682