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 1-7 filed on 10/24/2025 are pending. Claims 8-27, 38, & 43 are withdrawn from consideration as being drawn to a non-elected invention. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 1-7 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.
Regarding claim 1, the recitation of “probe set” in line 1 of the claim is unclear. How is the probe set structurally disposed relative to each other in space? Is the probe set a part of a kit or a composition? Does the probe set need to be in the same room, need to be in the same benchtop, in the same tube, etc. Finally, the recitation of “each probe pair within the first probe subset defines a target region … not identical to any other target region defined by any other probe pair within the second probe subset” in lines 10-14 of the claim is unclear. How does the target region effect the structure of the probe pairs? Do the probe pairs require full complementarity to the target region? In addition, the claim recites the limitation “the ligation arm” in lines 19 & 25 of the claim and it is unclear and there is insufficient antecedent basis for this limitation in the claim. It is unclear if “the ligation arm is referring back to “a 5’ phosphorylated ligation arm” or is referring to another ligation arm that does not require the 5’ end to be phosphorylated.
Regarding claim 2, the recitation of “target regions … defined by the probe pairs” in lines 3-5 of the claim is unclear. How does the target region effect the structure of the probe pairs? Do the probe pairs require full complementarity to the target region?
Regarding claim 3, the recitation of “a target region … defined by a probe pair” in lines 1-2 & 2-3 of the claim is unclear. How does the target region effect the structure of the probe pairs? Do the probe pairs require full complementarity to the target region?
Claims 4-7 are rejected due to their dependence on claim 1.
Claim 3 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. Claim 2 requires "neighboring target regions in the heavy strand defined by the probe pairs in the first probe subset overlap with neighboring complementary target regions in the light stand defined by the probe pairs in the second probe subset". Claim 3, which depends on claim 2, requires "a target region in the heavy strand defined by a probe pair from the first probe subset is followed by an overlapping target region in the light strand defined by a probe pair from the second probe subset". Therefore, it is unclear how “followed by overlapping target region” recited in claim 3 further limits “overlap with neighboring complementary target regions” recited in claim 2. 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.
Response to Arguments
The response traverses the rejection. The response asserts that those skilled in the art understand the metes and bounds of the claims when read in light of the specification and that the specification describes what a “probe set” is at paragraphs [0090] to [0100] stating that a probe set is for sequencing mitochondrial DNA and further that as the probe set is comprised of a plurality of probe pairs, the probe set is a composition made up of a plurality of probe pairs. This argument has been thoroughly reviewed but was not found persuasive as it is noted that the features upon which applicant relies (i.e., the probe set is a composition made up of a plurality of probe pairs) are not recited in the rejected claim(s). 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, 26 USPQ2d 1057 (Fed. Cir. 1993).
The response also asserts that the language regarding “target region”, the specification states “[t]he sequence between the ligation probe and the extension probe of a probe pair is said to be ‘captured’ or ‘defined’ by the probe pair and that the sequence between the ligation probe and the extension probe is also called the ‘target region’ of the probe pair” at paragraph [0091] of the instant specification. Further, the response asserts the those skilled in the art understand that the “target region” is defined as the sequence between the ligation probe and the extension probe of a probe pair. This argument has been thoroughly reviewed but was not found persuasive as it is noted that the features upon which applicant relies (i.e., the target region as the sequence between the ligation probe and the extension probe) are not recited in the rejected claim(s). 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, 26 USPQ2d 1057 (Fed. Cir. 1993). Further, it is unclear how target region effects the structure of the probe pairs.
The response also asserts that claim 3 further limits the elements of claim 2 as while claim 2 states that there is overlap between probe pairs of the first probe subset and the second probe subset, claim 2 does not define the order of the target regions. Further, the response asserts that claim 3 states “a target region in the heavy strand defined by a probe pair from the first probe subset is followed by an overlapping target region in the light strand defined by a probe pair from the second probe subset” which defines the order of the target regions. This argument has been thoroughly reviewed but was not found persuasive as claim 2 recites that “are designed such that neighboring target regions … overlap with neighboring complementary target regions” in lines 2-4 of the claim in which neighboring provides a sense of order of the target regions. Therefore, it is unclear how “followed by overlapping target region” recited in claim 3 further limits “overlap with neighboring complementary target regions” recited in claim 2.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 101
Claims 1-4, 6, & 7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature without significantly more. This judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
The unpatentability of natural products was confirmed by the U.S. Supreme Court in Association for Molecular Pathology v. Myriad Genetics, Inc., , 133 S. Ct. 2107, 2116, (2013).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1). The claims were then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)]. The claims were then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)]. In the absence of a step(s) or element(s) that integrate the JE into a practical application, the additional elements/steps have been considered to determine whether they add significantly more to the JE (STEP 2B) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)]. It was found that the present claims fail to meet the elements required for patent eligibility.
The claims are directed to a nucleic acid probe set and as such are directed to products. Accordingly, the claims are directed to one of the four statutory categories of invention.
The claims are drawn to nucleic acid probes including DNA, which comprise a first probe subset and a second probe subset that each comprise a plurality of probe pairs in which each probe pair within each probe subset comprise a ligation probe and an extension probe. Each ligation and extension probe are fragments of naturally occurring sequences. As such the claims are directed to a product of nature which is a judicial exception.
This judicial exception is not integrated into a practical application because the nucleic acid molecules encompassed by the claims convey the same genetic information as their naturally occurring counterparts. The Supreme Court has made clear "separating [DNA] from surrounding genetic material is not an act of invention" Myriad, 133 S. Ct. at 2117. In Myriad v. Ambry CAFC 2014-1361,1366, December 17, 2014, the CAFC further (regarding a claim directed to a pair of primers) stated “In fact, the naturally occurring genetic sequences at issue here do not perform a significantly new function. Rather, the naturally occurring material is used to form the first step in a chain reaction—a function that is performed because the primer maintains the exact same nucleotide sequence as the relevant portion of the naturally occurring sequence. One of the primary functions of DNA’s structure in nature is that complementary nucleotide sequences bind to each other. It is this same function that is exploited here—the primer binds to its complementary nucleotide sequence. Thus, just as in nature, primers utilize the innate ability of DNA to bind to itself.”
The detection agents encompassed by the claims include nucleic acid probes that hybridize to mitochondrial genomic DNA. None of these molecules or cells are patent eligible, whether isolated or not, pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics Inc., US (June 13, 2013). Accordingly, the claims are rejected as being directed to non-patentable subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that the probes recited in the present claims have a changed physical form as compared to their natural counterpart demonstrating markedly different characteristics from what exists in nature and further that as the probe pairs are not directed to nature-based products the probe set as a whole is not directed to a product of nature. Specifically, the response asserts that the eligibility of claims 1-7 can be completed through a streamlined analysis of step 2A as the ligation probe comprises the ligation arm that is an oligonucleotide “substantially complementary to a sequence at the 5’ border (a first end) of a target region” and the ligation probe also comprises a first primer annealing sequence that is not a product of nature. Further, the response asserts that similarly the extension probe comprises the extension arm that is “substantially complementary to a sequence of the 3’ border (a second end) of the target region” and the extension probe also comprises a second primer annealing sequence that is not a product of nature. This argument has been thoroughly reviewed but was not found persuasive as the claim 1, and dependent claims 2-4, 6, & 7, do not specifically exclude the first primer annealing sequence and the second primer annealing sequence, of the ligation and extension probes respectively, as being complementary to the target regions and therefore encompassing a product of nature. However, dependent claim 5 requires that the first and second primer annealing regions comprise a common nucleotide sequence therefore defining a structure that would require a non-naturally occurring sequence to be a part of the ligation and extension probes.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
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.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jian (CN105779590 (A), July 2016), machine translation obtained from Science & Technical Information Center (STIC).
Regarding amended claim 1, Jian teaches a probe set and kit for detecting human mitochondrial genes that is capable of capturing all mitochondrial genes (target regions defined by the first and second probe subset in combination cover the entirety of the mitochondrial DNA) and comprises 213 oligonucleotide probes with SEQ ID NO. 1-213, in which SEQ ID NO. 34 (from positions 52 to 72) encompasses SEQ ID NO. 14, human mitochondrial DNA ligation arm of a ligation probe, from the instant application (ligation probe comprises 5’-phosphroylated ligation arm complementary to the DNA target sequence), and SEQ ID NO. 29 (from positions 23 to 42) encompasses SEQ ID NO. 15, human mitochondrial DNA extension arm of an extension probe, from the instant application (extension probe comprises target specific extension arm) and that the probe set detects the whole mitochondrial genome sequence comprising the heavy and light chains (probe pair comprises a ligation probe and an extension probe and adjacent pairs of probes designed to target heavy and light strand of mtDNA) (paragraph [0004] lines 1-3; paragraph [0008] lines 1-3; paragraph [0009] lines 1-3; paragraph [0016] lines 1-3; paragraph [0029] lines 1-6; sequence listing). In addition, Jian teaches that the probes are synthesized to bind to primer sequences (probes comprise a primer annealing sequence) to use PCR to amplify the probes to capture the entirety of the mitochondrial DNA (paragraph [0029] lines 1-6; paragraph [0031] lines 1-4).
Jian does not teach the ligation probe comprising a ligation arm also comprises a first primer and that the extension probe comprising the extension arm comprises a second primer annealing sequence.
Jian does teach that the probes, ligation probe comprising a ligation arm and extension probe comprising an extension arm, are synthesized to bind to primer sequences (probes comprise a primer annealing sequence) to use PCR to amplify the probes to capture the entirety of the mitochondrial DNA (paragraph [0029] lines 1-6; paragraph [0031] lines 1-4).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a first primer annealing sequence to a ligation probe comprising a ligation arm and a second annealing primer sequence to an extension probe comprising an extension arm as taught by Jian because Jian teaches that the ligation and extension probes can bind to primer sequence to capture and amplify the mitochondrial DNA.
Regarding amended claim 2, Jian teaches that each probe, from SEQ ID NO. 1-213, was designed to move along the gene position to sequence the complete human mitochondrial genome sequence, in which there is a shift size of 3 bp between each probe (probe subsets are designed such that the first probe subset overlap (overlap by 3 bp) with neighboring complementary target regions) (paragraph [0029] lines 1-6).
Regarding claim 3, Jian teaches that each probe, from SEQ ID NO. 1-213, was designed to move along the gene position to sequence the complete human mitochondrial genome sequence, in which there is a shift size of 3 bp between each probe (the first probe subset is followed by an overlapping (overlap by 3 bp) target region from the second probe subset) (paragraph [0029] lines 1-6).
Regarding amended claim 4, it is noted that pg. 38 of the specification of the instant application teaches that the ligation and extension arms were designed in such a way that they would hybridize immediately upstream and downstream of capturing target cover regions ranged from 399 to 449 mer long in mtDNA.
Jian teaches a probe set and kit for detecting human mitochondrial genes that is capable of capturing all mitochondrial genes and comprises 213 oligonucleotide probes with SEQ ID NO. 1-213, in which SEQ ID NO. 34 (from positions 52 to 72) encompasses SEQ ID NO. 14, human mitochondrial DNA ligation arm of a ligation probe, from the instant application, and SEQ ID NO. 29 (from positions 23 to 42) encompasses SEQ ID NO. 15, human mitochondrial DNA extension arm of an extension probe, from the instant application (ligation and extension arms designed to anneal to a target region that is between 399 to 449 in length) (paragraph [0008] lines 1-3; paragraph [0009] lines 1-3; paragraph [0016] lines 1-3; paragraph [0029] lines 1-6; sequence listing).
Regarding claim 5 & amended claims 6 & 7, Jian teaches the use of universal PCR primers comprising different sequences (common nucleotide sequence for first primer annealing sequence hybridizing to first universal primer and common nucleotide sequence for the second primer annealing sequence hybridizing to a second universal primer) (paragraph [0031] lines 1-4). In addition, Jian teaches different barcodes (molecular tag) can be added to distinguish the samples comprising mitochondrial DNA (probes within the probe subset comprise a molecular tag sequence that is unique) (paragraph [0008] lines 1-3; paragraph [0009] lines 1-3; paragraph [0016] lines 1-3; paragraph [0020] lines 1-3; paragraph [0029] lines 1-6; sequence listing).
Response to Arguments
The response traverses the rejection. The response asserts that Jian does not teach each and every element of claim 1 and specifically, Jian does not teach a plurality of probe pairs, where each probe pair comprises a ligation probe comprising a first primer annealing sequence and a 5’-phosphorylated ligation arm wherein the ligation arm is substantially complementary to a first end of the target region on the mitochondrial DNA defined by the probe pair and an extension probe comprising an extension arm and a second primer annealing sequence wherein the extension arm is substantially complementary to a second end of the target region on the mitochondrial genomic DNA defined by the probe pair. Further, the response asserts that while not included in the elements of claim 1, the SEQ ID NOs referenced that are disclosed in Jian are not the full-length probes of the instant claims and are only the sequences of the ligation arm of the ligation probe and the extension arm of the extension probe and that, in contrast, Jian does not teach a probe comprising a first primer annealing sequence and a ligation arm and a probe comprising a second annealing sequence and an extension arm. These arguments have been thoroughly reviewed but were not found persuasive as discussed above, as necessitated by amendment, Jian teaches amended claim 1. Specifically, Jian teaches a probe set and kit for detecting human mitochondrial genes that is capable of capturing all mitochondrial genes (target regions defined by the first and second probe subset in combination cover the entirety of the mitochondrial DNA) and comprises 213 oligonucleotide probes with SEQ ID NO. 1-213, in which SEQ ID NO. 34 (from positions 52 to 72) encompasses SEQ ID NO. 14, human mitochondrial DNA ligation arm of a ligation probe, from the instant application (ligation probe comprises 5’-phosphroylated ligation arm complementary to the DNA target sequence), and SEQ ID NO. 29 (from positions 23 to 42) encompasses SEQ ID NO. 15, human mitochondrial DNA extension arm of an extension probe, from the instant application (extension probe comprises target specific extension arm) and that the probe set detects the whole mitochondrial genome sequence comprising the heavy and light chains (probe pair comprises a ligation probe and an extension probe and adjacent pairs of probes designed to target heavy and light strand of mtDNA) (paragraph [0004] lines 1-3; paragraph [0008] lines 1-3; paragraph [0009] lines 1-3; paragraph [0016] lines 1-3; paragraph [0029] lines 1-6; sequence listing). However, Jian does teach that the probes, ligation probe comprising a ligation arm and extension probe comprising an extension arm, are synthesized to bind to primer sequences (probes comprise a primer annealing sequence) to use PCR to amplify the probes to capture the entirety of the mitochondrial DNA (paragraph [0029] lines 1-6; paragraph [0031] lines 1-4). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a first primer annealing sequence to a ligation probe comprising a ligation arm and a second annealing primer sequence to an extension probe comprising an extension arm as taught by Jian because Jian teaches that the ligation and extension probes can bind to primer sequence to capture and amplify the mitochondrial DNA.
The response also asserts that since claims 2-7 depend from independent claim 1, and independent claim 1 is not anticipated by Jian, claims 2-7 cannot be anticipated by Jian. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 1-7 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/ Primary Examiner, Art Unit 1682