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 .
Election/Restrictions
Applicant’s election without traverse of Group II and cancellation of claims 1-15 in the reply filed on June 4, 2026 is acknowledged.
Claim(s) 16-32 is/are currently pending and examined herein.
Priority
Claim to benefit of provisional application 63/447,847 is acknowledged and the effective filing date of the instant application is considered to be February 23, 2023.
Claim Objections
Claim 23 is objected to because of the following informalities: improper grammar. The sentence lacks an article before the term “3’ end” such as ‘a’ or ‘the.’ Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim(s) 16-32 is/are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to methods of determining a level of a condition of an individual using comparison of jagged end metrics. Claim 1 recites the steps of measuring a first strand-specific classification; determining a jagged end value; comparing the jagged end value to a reference value, and determining a level of a condition of an individual using the comparison.
The claimed condition is required to possess certain characteristics in order to perform the method as recited. It must be capable of being determined using values derived from classifications of properties of the ends of a plurality of nucleic acid molecules.
In the instant case, the claims do not set forth the conditions in terms of sufficient relevant identifying characteristics. The claims encompass the determination of any conditions. Only claims 21, 31, and 32 describe specific conditions (cancer, nuclease activity deficiency). The specification does not provide a limiting definition of ‘condition,’ but allows that:
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The National Cancer Institute defines ‘condition’ as follows (accessed at https://www.cancer.gov/publications/dictionaries/cancer-terms/def/condition):
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Therefore, the size of the genus of ‘condition’ is very large, encompassing conditions with wide variety in cause, pathology, and affected tissues, including: broken bones, infections, allergies, kidney stones, anatomical differences such as scoliosis, cancer, pregnancy, etc. Claims which restrict the types of condition still encompass a large genus – there are many types of cancer and many types of nuclease activity deficiency.
The specification allows for any type of condition, but only a subset are explicitly mentioned, including cancer, transplantation, pregnancy, and autoimmune disorders (for example, in par. 42, 56-57, 108). Examples are provided only for hepatocellular carcinoma (par. 127 - 154) and nuclease activity deficiency of DNaseI, DNase1L3, and DFFB (par. 156-164).
The specification provides written description for the following conditions which can be determined using the claimed method: hepatocellular carcinoma (par. 127 - 154) and nuclease activity deficiency of DNaseI, DNase1L3, and DFFB (par. 156-164). The specification does not describe any other species within the claimed genus to show possession of those species.
Regarding the genus of conditions, the specification does not describe any structural features of the disclosed conditions which would have been expected to be shared by all members of the claimed genus. The specification does not describe physiological (physical and/or chemical) characteristics of the disclosed conditions that would be shared by members of the claimed genus. All members of the genus have the same function, i.e., they are conditions possessed by an individual which may be determined through the claimed method. The level of knowledge and skill in the art does not allow those skilled in the art to structurally envisage or recognize additional members of the claimed genus. Because the species within the claimed genus are expected to vary unpredictably from the structure of the conditions disclosed in the specification, the disclosed conditions are not a “representative number” of species within the claimed genus.
Because the conditions are not representative of the entire claimed genus, and the specification does not disclose structural features shared by members of the genus, the description of the conditions would not have put the applicant in possession of common structural attributes or features shared by members of the genus that structurally distinguish the members of the genus from non-members of the genus at the time of filing. Thus, the description of conditions is not sufficient to describe the claimed genus of conditions. Accordingly, the specification does not provide a representative number of species or sufficient common structural features to show that the applicant would have been in possession at the claimed genus as a whole at the time of filing.
Regarding the genus of conditions, the level of knowledge and skill in the art does not allow those skilled in the art to structurally envisage or recognize all pertinent conditions, because it is known that the medical term ‘conditions’ encompasses physiological states which are not known to have an impact on the fragmentation of DNA (for example, gout, broken bone, scoliosis, etc.). Therefore, those skilled in the art would have recognized that the specification’s disclosure of conditions consisting of hepatocellular carcinoma and nuclease activity deficiency of DNaseI, DNase1L3, and DFFB would not have put the applicant in possession of determining any type of condition at the time of filing. Thus, the specification does not describe sufficiently detailed, relevant characteristics to show that the applicant was in possession of the claimed genus of determination of any type of condition through the claimed method.
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 16-21, 23, 25-28, and 30 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.
Claims 16-21 are rejected for the recitation of ‘measurement of a … classification of a property’ in claim 16, as being indefinite. The meaning of the limitation is unclear, because ‘measuring’ may be plainly defined as ‘quantifying,’ but the specification allows that ‘classification’ may include ‘any number(s) or other character(s) that are associated with a particular property of a sample’ (par. 52). In the case that the classification is non-numerical (for example a binary classification of an end as blunt or overhanging), it is not clear what is meant by ‘measuring.’ As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement. If what was meant is that there is a step of ‘determining a … classification of a property,’ or simply “measuring a property…,” the claim must be amended to reflect that meaning. For the purposes of compact prosecution, the claim is interpreted to mean that a numerical or non-numerical value is determined in this step.
Claims 16-21 are rejected for the recitation of ‘a strand-specific classification’ in line 9 of claim 16, and ‘the strand-specific classification’ in claim 18 as being indefinite. It is not clear whether ‘a strand-specific classification’ is the same as the ‘first strand-specific classification’ recited in line 8, or if it represents another strand-specific classification. Therefore, it is not clear which ‘strand-specific classification’ claim 18 refers to. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 16-21 are rejected for the recitation of ‘determining a jagged end value using the first strand-specific classifications of the plurality of nucleic acid molecules’ in claim 16, as being indefinite. Because the determination of ‘a jagged end value’ occurs for each nucleic acid molecule, but this step recites that the determination occurs using a plurality of ‘classifications of the plurality of nucleic acid molecules,’ it is unclear whether a single jagged end value is determined for the plurality of nucleic acid molecules, or if a jagged end value is determined for each nucleic acid molecule (using its respective first strand-specific classification), or both. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 17, 19, and 20 are rejected for the recitation of “wherein determining the jagged end value uses the second strand-specific classifications” in claim 17, as being indefinite. The determination of ‘the jagged end value’ occurs for each nucleic acid molecule and requires multiple classifications. However, the claim recites measuring a single classification per nucleic acid molecule (‘a second single strand-specific classification’). It is unclear whether a single jagged end value is determined for the whole plurality of nucleic acid molecules, for a specific subset of the plurality of nucleic acid molecules, or if a jagged end value is determined for each nucleic acid molecule (using its respective first strand-specific classification), or both. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim 23 is rejected for the recitation of ‘the first strand has [a] 3’ end at the first end, and the first strand overhangs the second strand’ as indefinite. All DNA strands should have a 3’ end. It is therefore unclear what, if any, additional meaning was intended by the claim. If the applicant meant that the first strand overhangs the second strand at the 3’ end, the claim must be amended to reflect that meaning. For the purposes of compact prosecution, this limitation is interpreted to mean that there is a 3’ overhang on the first strand.
Claim 25 is rejected for the recitation of ‘generating the value of the end motif parameter uses the second amount’ as indefinite. As the claim on which it depends, claim 22, already recites the use of a first amount used to generate the end motif parameter, it is not clear whether the parameter generated by claim 25 uses both the first and second amount to generate the parameter, or whether claim 25 intends to replace the first amount with the second amount in generating the parameter. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claim 26 is rejected for the recitation of ‘a third sequence end motif’, ‘a fourth sequence end motif,’ and ‘a second combination’ of the third and fourth sequence end motifs as being indefinite. Claim 25 also recites ‘a third sequence end motif’, ‘a fourth sequence end motif,’ and ‘a second combination’ of a third sequence end motif and a fourth sequence end motif.’ It is not clear whether these represent the same third and fourth sequence end motifs and second combinations. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
Claims 27, 28, and 30 are rejected for the recitation of “wherein determining the first amount comprises determining the first amount…” as being indefinite. For example, it is unclear whether the first and second ‘the first amount’ recited in line 6 of claim 27 are meant to replace the ‘first amount’ of claim 22, or if they’re meant to be used together, or if there’s some other meaning intended by the claims. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter so as to avoid infringement.
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 16-32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4, Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite a correlation between the jagged end values of an individual and the level of a condition. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas.
Claims 16-21 recite steps of “determining a jagged end value” using classifications obtained in a previous step. Neither the specification nor the claims set forth a limiting definition for “determining” and the claims do not set forth how this step is accomplished. This “determining” step broadly encompasses mental processes. For example, one may “determine” a jagged end value by looking at a classification (e.g. “blunt end”) and thinking about what value would apply to such a classification (e.g. blunt ends could be determined to have a jagged end value of “0,” 5’ overhangs could be determined to have a jagged end value of “1,” etc.). Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Claims 16-32 recite steps of “comparing” the jagged end value(s) and/or end motif parameter(s) to reference value(s). Neither the specification nor the claims set forth a limiting definition for “comparing” and the claims do not set forth how this step is accomplished. The “comparing” step broadly encompasses mental processes. For example, one may “compare” values by looking at data and thinking about whether the jagged end value is different than a reference value. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Claims 16-32 recite a step of “determining a level of a condition.” Neither the specification nor the claims set forth a limiting definition for “determining” and the claims do not set forth how this step is accomplished. This “determining” step broadly encompasses mental processes. For example, one may “determine” a level of a condition by looking at a jagged end value and a reference value and thinking about what the comparison indicates regarding the level of a condition. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Claims 22-32 recite steps of “determining” sequence end motifs. Neither the specification nor the claims set forth a limiting definition for “determining” and the claims do not set forth how this step is accomplished. This “determining” step broadly encompasses mental processes. For example, one may “determine” a sequence end motif by looking at sequencing reads and thinking about what motifs are present. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Claims 22-32 recite steps of “generating a value of an end motif parameter.” Neither the specification nor the claims set forth a limiting definition for “generating” and the claims do not set forth how this step is accomplished. This “generating” step broadly encompasses mental processes. For example, one may “generate” a value of an end motif parameter by looking at an amount of nucleic acid molecules having combinations of sequence motifs and thinking about what value would apply to such a classification (e.g. an undetectable level of molecules having combination X may be mentally assigned a value of “0” as a parameter). Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exception(s) into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or a technological field;
An additional element that applies or used a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing;
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions, the claims recite steps of “measuring” strand-specific classifications and/or “determining” amounts of nucleic acids having combinations of sequence end motifs. These steps are not considered to integrate the judicial exceptions into a practical application because they merely adds insignificant extra-solution activity (data gathering) to the judicial exceptions.
In addition to the judicial exceptions, the claims recite that the jagged end values are comprised in a vector with a plurality of elements including several specific classifications. These steps are merely instruction to apply the exception in generic ways. Thus, the administration steps do not integrate the mental analysis step into a practical application.
In addition to the judicial exceptions, the claims recite wherein clauses delimiting the values used for determinations and describing qualities of various limitations (e.g. “wherein the condition is nuclease activity deficiency”, “wherein the first end comprises a blunt end,” etc.). These steps are merely instruction to apply the exception in generic ways. Thus, the administration steps do not integrate the mental analysis step into a practical application.
Step 2B: Evaluate Whether the Claim Provides and Inventive Concept
In addition to the judicial exceptions, the claims recite steps of “measuring” strand-specific classifications and/or “determining” amounts of nucleic acids having combinations of sequence end motifs. These steps do not amount to significantly more because they simply append well-understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
In addition to the judicial exceptions, the claims recite that the jagged end values are comprised in a vector with a plurality of elements including several specific classifications. This does not amount to significantly more because it simply appends well-understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
In addition to the judicial exceptions, the claims recite wherein clauses delimiting the values used for determinations and describing qualities of various limitations. These intended uses and other limitations do not amount to significantly more because they simply append well-understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The steps are recited a high level of generality. Measuring strand-specific classifications and/or determining amounts of nucleic acids having combinations of sequence end motifs merely instruct a scientist to use any known technique for measuring strand-specific classifications and/or determining amounts of nucleic acids having combinations of sequence end motifs. The claims do not require the use of any particular non-conventional reagents or equipment or methodology. When recited at this high level of generality, there is no meaningful limitation that distinguishes these steps from well-understood, routine, and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well-understood, routine, and conventional nature of additional elements because it teaches that the additional elements are well-known or commercially available. For example, the specification teaches the following:
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Further, it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, and conventional activity in the life science arts when they are claimed in a merely generic manner (e.g. at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 16, 18, and 21 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Jiang et al. (published Aug 2020; Jiang et al. Genome Res. 2020 Aug;30(8):1144-1153).
Regarding claim 16, Jiang recites a method of analyzing a biological sample comprising a plurality of nucleic acid molecules that are cell-free, each nucleic acid molecule of the plurality of nucleic acid molecules being double-stranded with a first strand and a second strand, the biological sample being obtained from an individual, at least some of the nucleic acid molecules of the plurality of nucleic acid molecules having nucleotides on one strand that have no complementary portion on the other strand (Abstract). Jiang recites that the method comprises, for each nucleic acid molecule of the plurality of nucleic acid molecules: measuring a first strand-specific classification of a property of a first end of the nucleic acid molecule and determining a jagged end value using the first strand-specific classifications of the plurality of nucleic acid molecules (pg. 1145, “Principle for detecting jagged ends” and pg. 1146, “High-resolution jagged end analysis”); comparing the jagged end value to a reference value and determining a level of a condition of the individual using the comparison (pg. 1149: “Diagnostic applications of plasma DNA jaggedness for HCC detection”).
Jiang’s strand-specific classification is the determination of the property of methylation level at the ends of a fragment, which is indicative of whether the first strand or the second strand overhangs the other (pg. 1145, “Principle for detecting jagged ends” and pg. 1146, “High-resolution jagged end analysis”). The jagged end value is the jag index abbreviated either “JI-U” (pg. 1145, last lines of “Principle for detecting jagged ends”) or “JI-M” (pg. 1146, last lines of col. 2). The condition is, for example, hepatocellular carcinoma (pg. 1149: “Diagnostic applications of plasma DNA jaggedness for HCC detection”).
Regarding claim 18, Jiang recites that the strand-specific classification indicates the length of an overhang (pg. 1147, col. 1, 1st full par.).
Regarding claim 21, Jiang recites that the condition is nuclease activity deficiency (pg. 1149, col. 2, 2nd full par.).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 17, 19, and 20 are rejected under 35 U.S.C. 103 as unpatentable over Jiang et al. (published Aug 2020; Jiang et al. Genome Res. 2020 Aug;30(8):1144-1153), as applied to claim 16 above, and further in view of Troll et al. (published Dec 27, 2019; Troll et al. BMC Genomics. 2019 Dec 27;20(1):1023).
As discussed in the 35 U.S.C. 102(a)(1) rejection above, Jiang recites the limitations of claim 16.
Regarding claim 19, Jiang recites the comparison of a vector of a plurality of jagged end values to a reference vector for the determination of a level of a condition (pg. 1148, col. 2, last full par.). Here, the vector of a plurality of jagged end values is a series of cumulative fetal JI-M values compared to a series of cumulative maternal JI-M values, and the condition is pregnancy. For clarity, please note that as the specification lacks specific and limiting definitions for the terms ‘vector’ and ‘element,’ the interpretation of the limitations of claim 19 includes the following plain meanings. ‘Vector’ is interpreted to mean a list of a series of values, each value of such a list or series is considered an ‘element.’ These interpretations are consistent with the meaning as used in the specification (for example, in par. 172).
Regarding claim 17, Jiang does not recite that the method further comprises, for each nucleic acid molecule of the plurality of nucleic acid molecules, measuring a second strand-specific classification of the second end of the nucleic acid molecule, wherein determining the jagged end value uses the first and/or the second strand-specific classifications.
Regarding claim 19, Jiang does not recite that the plurality of elements comprising the jagged end value(s) in the vector includes amounts of nucleic acid molecules in the following classifications: blunt-ended at the first end and blunt-ended at the second end, 5' overhang at the first end and blunt-ended at the second end, 3' overhang at the first end and blunt-ended at the second end, 5' overhang at the first end and 3' overhang at the second end, 5' overhang at the first end and 5' overhang at the second end, and 3' overhang at the first end and 3' overhang at the second end.
Regarding claim 17, Troll teaches a method which is capable of determining a second strand-specific classification at the second end of a nucleic acid molecule (pg. 5, col. 2; Fig. 3). In this case, unlike many other methods, Troll’s method allows for the determination of both 3’ and 5’ native ends, including sequence and length information (Fig. 3). This information can be determined at both ends, as shown by the sequence determinations of forward and reverse reads in Fig. 2e (pg. 4).
Regarding claim 19, Troll teaches methods capable of determining the following classifications: blunt-ended at the first end and blunt-ended at the second end, 5' overhang at the first end and blunt-ended at the second end, 3' overhang at the first end and blunt-ended at the second end, 5' overhang at the first end and 3' overhang at the second end, 5' overhang at the first end and 5' overhang at the second end, and 3' overhang at the first end and 3' overhang at the second end (Fig. 2e, Fig. 3). In this case, sequence coverage, read position, and base composition reveal the presence of overhangs and blunt ends (i.e. ‘strand-specific classifications’) on either end and on either strand of a nucleic acid molecule (pg. 5, col. 1, last par. – pg. 6, col. 1, par. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Jiang and Troll, in order to utilize a fast, simple, and efficient sequencing method that does not alter the native ends of nucleic acid molecules (Troll: pg. 2, col. 2, 1st full par.). One would have had reasonable expectation of success because Troll demonstrates that the determination of the appropriate classifications is possible (Troll: Fig. 2e, 3), and Jiang demonstrates the use of similar data in determining a level of a condition of an individual (pg. 1149: “Diagnostic applications of plasma DNA jaggedness for HCC detection”).
Regarding claim 20, Jiang recites a plurality of elements comprising a classification of nucleic acid molecules having sizes in one or more size ranges (pg. 1148, col. 2, last full par.)
Claims 22-32 are rejected under 35 U.S.C. 103 as unpatentable over Harkins et al. (published Feb 29, 2020; Harkins et al. Nucleic Acids Res. 2020 May 7;48(8):e47), in view of Troll et al. (published Dec 27, 2019; Troll et al. BMC Genomics. 2019 Dec 27;20(1):1023) and further in view of Lo et al. (published Apr 9, 2021; Lo et al. 2021 Apr 9;372(6538):eaaw3616).
Regarding claim 22, Harkins teaches a method of analyzing a biological sample comprising a plurality of nucleic acid molecules, each nucleic acid molecule of the plurality of nucleic acid molecules being double-stranded with a first strand and a second strand, at least some of the nucleic acid molecules of the plurality of nucleic acid molecules having nucleotides on one strand that have no complementary portion on the other strand, the biological sample being obtained from an individual (Abstract). Harkins teaches that the method comprises, for each nucleic acid molecule of the plurality of nucleic acid molecules: determining a first sequence end motif of the first strand at a first end of the nucleic acid molecule, and determining a second sequence end motif of a second strand at a first end of the nucleic acid molecule (Harkins: pg. 2, col. 1, 2nd par.);
Regarding claims 22-32, Harkins teaches determining amounts of nucleic acid molecules having combinations of sequence end motifs and generating a value of an end motif parameter using those amounts (pg. 9, col. 2 – pg. 10, col. 1; Figure 4, B and E). In Harkins, the amounts are the amounts of particular base calls, the end motif parameter is represented as a mean percentage of those base calls at a given position, and the sequence end motifs are any given combination of bases 1-6 in the overhang (Supplementary Figure 4, legend). For any specific base parameter at any given position or sets of positions, the reference value for comparison could be the percentage of the other possible bases at the same position(s).
Regarding claims 23 and 24, Harkins teaches that the first strand may have a 3’ overhang and that the first end comprises a blunt end (Figures 2 and 4).
Regarding claims 27-30, Harkins teaches for each nucleic acid molecule of the plurality of nucleic acid molecules, measuring (pg. 2, col. 1, 2nd par.): a first strand-specific classification of a first end, a second strand-specific classification of a second end, an amount of at least one sequence end motif at a first end, and an amount of at least one sequence end motif at a second end. Harkins determines the sequence at 3’ or 5’ overhangs (pg. 9, last par. – pg. 10, 1st par.; Figure 4, B and E) and at blunt ends (Supplementary Figures 2, 4), thereby determining (at either end) both the strand-specification classification and the amounts of sequence end motifs. For example, Harkins determines a preference in DNaseI-treated samples for residues other than cytosine in 5’ overhangs and a preference for thymine residues in 3’ overhangs (pg. 9, col. 2, last par.), and a preference in MNase-treated samples for blunt ends or A/T rich motifs on 5’ overhangs (pg. 10, col. 1). Further, Harkins reports sequence determination of both blunt ends (Supplementary Figures 2, 4), which contain a first and a second sequence end motif (in the form of complementary sequences) on a single end.
Regarding claims 22-32, Harkins does not explicitly teach determination of classifications on two ends of the same molecule.
Troll teaches a method which is capable of determining a strand-specific classifications at both ends of a nucleic acid molecule (pg. 5, col. 2; Fig. 3). In this case, unlike many other methods, Troll’s method allows for the determination of both 3’ and 5’ native ends, including sequence and length information (Fig. 3). This information can be determined at both ends, as shown by the sequence determinations of forward and reverse reads in Fig. 2e (pg. 4). In this case, sequence coverage, read position, and base composition reveal the presence of overhangs and blunt ends (i.e. ‘strand-specific classifications’) on either end and on either strand of a nucleic acid molecule (pg. 5, col. 1, last par. – pg. 6, col. 1, par. 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Harkins and Troll, in order to utilize a fast, simple, and efficient sequencing method (Troll: pg. 2, col. 2, 1st full par.) which is able to retain strand information from dsDNA and accurately characterize template molecules (pg. 9, col. 2, last par.). One would have had reasonable expectation of success because Troll demonstrates that the determination of the appropriate classifications is possible (Troll: Fig. 2e, 3).
Regarding claims 22-32, Harkins and Troll do not explicitly teach determining amounts of nucleic acid molecules having specific combinations of both the first and second strand sequence end motifs on the same end of a molecule to determine a level of a condition. However, Harkins does teach that nucleases demonstrate sequence preferences which result in preferential motifs at both the 3’ and 5’ ends of a cut (pg. 9, col. 2 – pg. 10, col. 1; Supplementary Figure 4), and Troll suggests the investigation of base composition at 5’ and 3’ ends for elucidation of the nature of overhangs, including potentially the identity of nucleases which generate them (pg. 10, col. 1, 2nd par.).
However, a given end of a nucleic acid molecule has only a two sequence end motifs (on either strand). Given that there are a finite number of solutions (i.e. analysis of the first or second or a combination of both), and there is no evidence of unexpected results, it would have been obvious to a person with ordinary skill in the art to try enumerating the combination of both a first and second sequence motif at a given end of a DNA fragment. One would have been motivated to do so in order to elucidate the mechanisms of cell-free DNA fragmentation or to reveal the precise effects of DNA digestion or cleavage (Harkins: pg. 1, col. 2, 1st full par.; Troll: pg. 10, col. 1, 2nd par.). A person with ordinary skill in the art would have had a reasonable expectation of success because Troll demonstrates obtaining forward and reverse reads of the same molecules (Troll: Fig. 2e), which would allow the sequence motifs of both strands to be determined.
Regarding claims 22-32, Harkins and Troll do not explicitly teach determining a level of a condition using comparisons between end motif parameter values.
Regarding claim 26, Harkins and Troll do not explicitly teach that the plurality of nucleic acid molecules is a first plurality of nucleic acid molecules, the biological sample comprises a second plurality of nucleic acid molecules, and the first plurality of nucleic acid molecules includes a subset of the second plurality of nucleic acid molecules.
Regarding claims 31 and 32, Harkins and Troll do not explicitly teach the determination of cancer and/or nuclease activity deficiency using strand-specification classifications and/or end sequence motifs. However, Troll does teach the use of sequence data for determining the nuclease responsible for cfDNA fragmentation (pg. 10, col. 1, par. 2), and that other relevant data generated by their method is associated with cancer (pg. 2, col. 1, 2nd par.; pg. 9, col. 2, 2nd to last par.
Regarding claims 22-32, Lo teaches determining a level of a condition of the individual using the comparison between an end motif parameter values (pg. 5-7: “Plasma DNA fragmentation and nuclease biology”; Fig. 4). For example, the comparison could be between the frequencies of DNase1L3-associated sequence end motifs in cancerous vs non-cancerous samples (pg. 6, col. 1-2). Lo also discusses that 5’ overhangs (a strand-specific classification) comprising “A” sequences (an end motif) differ in quantity between wildtype and Dffb-deficient mice (pg. 5, col 2).
Regarding claim 26, Lo teaches a first plurality of nucleic acid molecules which includes a subset of a second plurality of nucleic acid molecules (Fig. 4). In Lo, the first plurality would be total/global circulating DNA, and the second plurality would be fetal or cancer circulating DNA.
Regarding claims 31 and 32, Lo teaches the determination of cancer (Fig. 4) and/or nuclease activity deficiency (pg. 6, col. 2).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Harkins and Troll with the teachings of Lo in order to analyze biomarkers which may achieve maximal diagnostic power with a relatively small amount of DNA (Lo: pg. 6, col. 2). One would have had reasonable expectation of success because Lo reports that plasma DNA end motifs are known to change in cancer and other conditions (pg. 6, col. 1-2) and jagged end frequencies are correlated with various medical conditions such as pregnancy (pg. 7, col. 1, 1st par.).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 16-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Patent No. 12,595,511.
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods (claims 1-20). Both sets of claims require:
A sample comprising a plurality of nucleic acid molecules that are cell-free wherein each nucleic acid molecule of the cell-free plurality of nucleic acid molecules is double-stranded with a first strand and a second strand, at least some of the nucleic acid molecules of the plurality of nucleic acid molecules having nucleotides on one strand that have no complementary portion on the other strand (1-20)
Measuring a first strand-specific classification of a property of a first end and/or second strand of the nucleic acid molecule which indicates the length of an overhang (1, 13)
Determining a jagged end value using said classification (1, 13)
Comparing the jagged end value to a reference value to determine the level of a condition (1, 13)
Conditions comprising cancer (1)
Classification of nucleic acid molecules having sizes in one or more ranges (4-5)
Determining end sequence motifs (9, 10, 16-18)
Claims 16-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of co-pending Application No. 19/636,757.
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods (claims 1-28). Both sets of claims require:
A sample comprising a plurality of nucleic acid molecules that are cell-free wherein each nucleic acid molecule of the cell-free plurality of nucleic acid molecules is double-stranded with a first strand and a second strand, at least some of the nucleic acid molecules of the plurality of nucleic acid molecules having nucleotides on one strand that have no complementary portion on the other strand (1-28)
Measuring a first strand-specific classification of a property of a first end and/or second strand of the nucleic acid molecule which indicates the length of an overhang (2, 8, 17)
Determining a jagged end value using said classification (11, 16)
Comparing the jagged end value to a reference value to determine the level of a condition (12, 16, 28-29)
Conditions comprising cancer (14-15, 21-22)
Classification of nucleic acid molecules having sizes in one or more ranges (4-5)
Determining end sequence motifs (9, 10, 16-18)
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claimed are allowed.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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