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 I (claims 1-7 and 10-14) in the reply filed on October 24, 2025 is acknowledged.
Claims 8-9 and 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-7 and 10-14 are under examination.
Priority
The present application, filed on March 2, 2023, is a 371 of PCT/US2021/047506, filed on August 25, 2021 and claims priority to U.S. Provisional Patent Application 63/074101, filed on September 3, 2020.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 16. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms Qiagen, “Quiagen”, “Nuclisensm”, “Promegam”, Illumina, and Nanostring which each appear to be a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Claims 1-7 and 10-14 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Regarding claims 1, 2, 12, and 14, where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “nucleotides” in claims 1, 12, and 14 is used by the claim to mean “polynucleotides”, or “nucleic acids” while the accepted meaning is “a nucleotide consists of a sugar molecule (either ribose in RNA or deoxyribose in DNA) attached to a phosphate group and a nitrogen-containing base.” (National Human Genome Research Institute. Talking Glossary of Genomic and Genetic Terms, “Nucleotide”. https://www.genome.gov/genetics-glossary/Nucleotide) The term is indefinite because the specification does not clearly redefine the term.
Claim 10 recites the limitation "the milk to media ratio" in line 1. There is insufficient antecedent basis for this limitation in the claim. Furthermore, it is unclear whether claim 10 is intended to depend from claim 6 (part of the elected invention), or claim 8 (part of a withdrawn invention directed to a method of culturing breast-milk derived cells).
Claim 12 is rendered indefinite because it is unclear whether the claim term “copy number of a gene in the nucleotides” is intended to require quantifying copy number variation associated with a cancer (i.e. a breast cancer enriched gene aberration), or is intended to require quantifying the number of nucleic acid molecules per unit volume (as further required by claim 13).
Claims 2-7 and 10-14 are rejected as indefinite because they depend from and thus include the indefinite limitation(s) of the claims rejected above.
Claim Interpretation
The claim term “breast cancer enriched gene aberrations” has been interpreted herein as encompassing a very broad genus of differences between nucleic acid molecules obtained from a breast milk sample comprising breast cancer-derived nucleic acids and nucleic acid molecules obtained from a breast milk sample that does not comprise breast cancer-derived nucleic acids. Therefore, “a gene aberration” encompasses, for example, any mutation, difference in methylation or other covalent modification, or DNA damage that are “enriched” in the breast cancer derived sample relative to the control sample.
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 5-7 and 10-11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
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.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Step 2A Prong I
The claims are taken to be directed to a natural phenomenon and an abstract idea.
Claim 5 is directed to a method involving a judicial exception (an abstract idea, a comparison to control), the method comprising detecting a cancer marker in a breast milk sample by (i) extracting nucleotides from a breast milk sample, (ii) analyzing the nucleotides in the breast milk sample for gene expression and breast cancer enriched gene aberrations, (iii) quantifying the gene expression level and breast cancer enriched gene aberrations of a cancer marker, and (iv) detecting the cancer marker based on based on (iii), wherein the cancer marker is p63 and the gene expression level is compared to a control sample.
Claim 6 further recites that cancer is detected in the breast milk sample if the p63 expression is at least 1.5 times higher compared to the control sample. (i.e. a natural correlation between the presence/amount of a nucleic acid and the presence of cancer)
Claim 7 recites that the control sample is provided from the same patient.
Claim 11 recites that the control sample is provided by an average population data set.
A comparison to control is an abstract idea. (See MPEP 2106.04(a)(2)(III)(A); claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014).
A correlation that preexists in the human is an unpatentable phenomenon. The association between the presence of a cancer marker (i.e. the presence of cancer) and the gene expression level and breast cancer enriched gene aberrations of the cancer marker is a law of nature/natural phenomenon. The “detecting based on quantification” steps recited by the claims amount to no more than an instruction to apply the natural law. Furthermore, the detection based upon a comparison to control steps amount to no more than a mental step. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the natural law to a new and useful end.
Furthermore, the detection step recited by claim 6 is conditional upon the p63 (a cancer marker) expression level relative to a control sample: “if the p63 expression level increase is at least 1.5 times higher compared to the control sample, cancer is detected [in] the breast milk sample.” Therefore, the claim encompasses non-detection of cancer if the p63 expression level is not at least 1.5 times higher in the breast milk sample relative to the control sample. Therefore, the “detecting” steps do not require the process user to do anything in light of the correlation. These steps fail to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Step 2A Prong II
The exception is not integrated into a practical application. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. While the claims recite “extracting nucleotides from a breast milk sample”, “analyzing the nucleotides…for gene expression and breast cancer enriched gene aberrations”, and “quantifying the gene expression level and breast cancer enriched gene aberrations of a cancer marker”, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non-patent eligible elements, are sufficient to “transform the nature of the claims into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more than a statement of a natural principle for at least these reasons:
The claims do not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to extracting and measuring the abundance of particular nucleic acid cancer markers in breast milk are mere data gathering steps that amount to extra solution activity to the judicial exceptions. The extracting, analyzing, and quantifying steps do not require the use of any particular methods to accomplish these steps. Therefore, these steps tell users to measure the nucleic acid cancer markers by any methods known in the art. Additionally, the specification teaches that “in the methods herein described, DNA/mRNA may be detected and/or quantified using any DNA detection method known in the art (page 9, paragraph 6).
Quantifying the expression level and breast cancer enriched gene aberrations of cancer markers in breast milk was well known in the art at the time the invention was made. The prior art, for example, Too et al., US 2018/0230544 A1 teach methods comprising extracting RNA from breast milk (Too et al., paragraph 0065) and analyzing/quantifying expression levels of various cancer markers relative to control samples (Too et al., abstract). Too et al. additionally teach classifying samples into molecular subtypes Luminal A, Her2, and Triple Negative based upon the presence of cancer enriched mutations (e.g. triple negative, HER-2-/-, ER-/-, PR-/-) (Too et al., paragraph 0010).
Furthermore, Koker et al., “p63 Expression in Breast Cancer” Am J Surg Pathol 2004;28:1506-1512 (published 2004) teaches that as early as 2004, p63 was recognized in the art as a specific and sensitive marker for metaplastic carcinomas of the breast (i.e. breast cancer) (Koker et al., page 1511, column 1).
The claims do not require the use of any particular non-conventional reagents.
Furthermore, the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner 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. Ltd. 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);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546;
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); and
Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3 and 12-13 are rejected under 35 U.S.C. 102(a)(1) or 35 U.S.C. 102(a)(2) as being anticipated by Too et al., US 2018/0230544 A1, published August 16, 2018.
Regarding claim 1, Too et al. teach methods for detecting markers of breast cancer in bodily fluid samples (Too et al., Abstract), wherein the bodily fluid is a breast milk sample (Too et al., paragraph 0065).
Too et al. teach extracting nucleic acids from the sample, quantifying and analyzing the expression levels of breast-cancer associated genes (Too et al., Abstract and Figure 2; see below) as well as breast cancer enriched gene aberrations used to establish breast cancer subtypes (i.e. HER2, ER, PR, and HR) (Too et al., paragraphs 0027-0029).
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Regarding claim 2, Too et al. teach amplifying the extracted polynucleotides before the quantification step (Too et al., Figure 2).
Regarding claim 3, Too et al. teach detecting the cancer markers based on quantification of the gene expression (the expression levels of the various markers taught by Too et al.) and breast cancer enriched gene aberrations (i.e. the breast cancer enriched gene aberrations used to establish breast cancer subtypes HER2, ER, PR, and HR) (Too et al., Figure 2 and paragraphs 0027-0029).
Regarding claims 12-13, Too et al. teach quantifying the absolute copy number of various miRNA cancer markers (i.e. the copy number of a gene in the nucleotides) (Too et al., paragraph 0009 and 0082) per mL of sample (Too et al., paragraph 0107).
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 1-5, 7, and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Too et al., US 2018/0230544 A1, published August 16, 2018 in view of Thomas et al., “14-3-3 (sigma) regulates proliferation and differentiation of multipotent p63-positive cells isolated from human breastmilk” Cell cycle 10:2, 278-284; January 15, 2011, Hassiotou et al., “Expression of the pluripotency transcription factor OCT4 in the normal and aberrant mammary gland” Frontiers in Oncology April 2013; Volume 3; article 79, and Koker et al., “p63 expression in breast cancer; A Highly Sensitive and Specific Marker of Metaplastic Carcinoma” Am J Surg Pathol 2004; 28:1506-1512.
Regarding claim 1, Too et al. teach methods for detecting markers of breast cancer in bodily fluid samples (Too et al., Abstract), wherein the bodily fluid is a breast milk sample (Too et al., paragraph 0065).
Too et al. teach extracting nucleic acids from the sample, quantifying and analyzing the expression levels of breast-cancer associated genes (Too et al., Abstract and Figure 2; see below) as well as breast cancer enriched gene aberrations used to establish breast cancer subtypes (i.e. HER2, ER, PR, and HR) (Too et al., paragraphs 0027-0029).
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Regarding claim 2, Too et al. teach amplifying the extracted polynucleotides before the quantification step (Too et al., Figure 2).
Regarding claim 3, Too et al. teach detecting the cancer markers based on quantification of the gene expression (the expression levels of the various markers taught by Too et al.) and breast cancer enriched gene aberrations (i.e. the breast cancer enriched gene aberrations used to establish breast cancer subtypes HER2, ER, PR, and HR) (Too et al., Figure 2 and paragraphs 0027-0029).
Regarding claim 4, Too et al. do not teach that the cancer marker is p63.
However, Thomas et al. teach that p63-positive cells are present in human breastmilk (Thomas et al., page 279, column 1, paragraph 2 and figure 4). Additionally, Hassiotou et al. teach that cancer stem cells (CSCs) with elevated expression of stem cell markers OCT4, SOX2, and NANOG are present in lactating breast cancers (Hassiotou et al., page 7, column 2, paragraph 2-page 9, column 1, paragraph 2). Furthermore, Koker et al. teach that aberrant expression of p63 is a specific and sensitive marker for metaplastic carcinomas of the breast (i.e. is a breast cancer marker) (Koker et al., page 1511, column 1, paragraph 1).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the methods taught by Too et al. for detecting cancer markers in breast milk comprising extracting nucleic acids from human breastmilk, amplifying said nucleic acids, quantifying and analyzing the expression of cancer markers in the extracted nucleic acids to further comprise quantitation of expression of the breast cancer marker p63. The ordinary artisan would have been motivated to detect aberrant expression of p63 in breastmilk in the assay taught by Too et al. because of the teachings of Koker et al. that aberrant p63 expression is a sensitive and specific marker for breast cancer. The ordinary artisan would have had a reasonable expectation of success in detecting aberrant p63 expression in breastmilk because of the teachings of Thomas et al. that a population of multipotent, p63-positive cells is readily isolated from human breastmilk collected from healthy lactating mothers and because of the teachings of Hassiotou et al. that cancer stem cells are present in breastmilk samples from breast cancer patients.
Regarding claim 5, Koker et al. teach comparing p63 expression levels to a control (Koker et al., page 1508, column 2, paragraph 2).
Regarding claim 7, Koker et al. teach the control sample is provided from the same patient (Koker et al., page 1508, column 2, paragraph 2).
Regarding claims 12-13, Too et al. teach quantifying the absolute copy number of various miRNA cancer markers (i.e. the copy number of a gene in the nucleotides) (Too et al., paragraph 0009 and 0082) per mL of sample (Too et al., paragraph 0107).
Claims 6 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Too et al., Thomas et al., Hassiotou et al., and Koker et al. as applied to claims 1-5, 7, and 12-13 above, and further in view of Schisterman et al., “Youden Index and the optimal threshold for markers with mass at zero” Stat Med. 2008 January 30; 27(2):297-315.
Regarding claims 6 and 11, the method taught by Too et al., Thomas et al., Hassiotou et al., and Koker et al. do not teach a particular cutoff value of relative p63 expression for discriminating between a breast milk sample from a patient with cancer and a control sample or an average population dataset. However, Schisterman et al. teach routine methods for calculating an optimal threshold value for classifying subjects as healthy or diseased based upon receiver operating characteristic curve analysis wherein the biomarker values are measured in a population of healthy and a population of diseased individuals (Schisterman et al., page 297-298, paragraph 3).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have optimized a cutoff expression value (i.e. 1.5 times higher than the control) through routine calculations based upon a receiver operating characteristic curve analysis comprising comparing a population of diseased individuals to a population of healthy individuals.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Too et al., Thomas et al., Hassiotou et al., and Koker et al. as applied to claims 1-5, 7, and 12-13 above, and further in view of Zhang et al., “A genetic variant in p63 (rs17506395) is associated with breast cancer susceptibility and prognosis” Gene 535 (2014) 170-176, published December 4, 2013.
Regarding claim 14, the method taught by Too et al., Thomas et al., Hassiotou et al., and Koker et al. do not teach that detecting the cancer marker comprises detecting a mutation. However, Zhang et al. teach a single nucleotide polymorphism (SNP) in p63 that is associated with higher aberrant expression of p63 in breast cancers (Zhang et al., Figure 1).
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Furthermore, Zhang et al. teach the presence of the SNP is a biomarker for poor prognosis in breast cancer, with SNP homozygotes exhibiting poorer overall survival relative to both heterozygotes and reference allele homozygotes (Zhang et al., figure 2).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by Too et al., Thomas et al., Hassiotou et al., and Koker et al. for detecting cancer markers in breast milk comprising extracting nucleic acids from human breastmilk, amplifying said nucleic acids, quantifying and analyzing the expression of the breast cancer marker p63 to further comprise detecting the presence of the mutation rs17506395 in p63. The ordinary artisan would have been motivated to include detection of this mutation in p63 into the assay taught by Too et al., Thomas et al., Hassiotou et al., and Koker et al., because of the teaching of Zhang et al. that hetero- or homozygotes for the T/T allele at rs17506395 display higher expression of p63 in breast cancer samples, and further exhibit poorer prognosis relative to the population of breast cancer patients with the G/G reference genotype.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY MARK TURPIN whose telephone number is (703)756-5917. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682