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 the particular species that are: (I) the combination of genes that are ZNF807 and LOC100130331 which are female specific genes; and (II) the marker that is Flk-1/KDR, in the reply filed on 10/27/2025 is acknowledged.
It is noted that the elected EPC marker Flk-1/KDR is synonymous with VEGFR2 and CD309, and as such the species election requirement among the particular markers recited as Flk-1, KDR, VEGFR2, or CD309 (see page 4 of the Requirement of 07/29/2025) is withdrawn.
Claims 8, 69, 73 and 75 (requiring non-elected male specific genes), and claims 25, 68 and 74 (directed to genes that do not include the elected LOC100130331; i.e.: LOC100130331 does not appear among the particular female specific genes of Tables 1, 3 and 5) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/27/2025.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
The sequences in Table 19 (on page 32 of the clean Substitute Specification of 06/28/2023) and Table 21 (on page 48 of the clean Substitute Specification of 06/28/2023) are not identified by any sequence identifiers (i.e.: SEQ ID NO: ).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in the right column of each of Tables 19 and 21 ((on page 32 and page 48, respectively, of the clean Substitute Specification of 06/28/2023).
Here it is noted that where the right column is disclosed as “biomarker nucleotide seq target mRNA” of the left column “biomarker nucleotide seq probe”, because of the conventional presentation of nucleic acids in a 5’ to 3’ direction, the “target” is not in fact the reverse complement of the “probe”. For example, with regard to Table 19, the sequence in the first column (Code PSC 2102), while the left sequence (probe) is SEQ ID NO: 1:
5’-atcagaggcagttaagatccaatgt-3’
the right sequence is:
5’-TAGTCTCCGTCAATTCTAGGTTACA-3’
which is not the reverse complement of SEQ ID NO: 1, nor is the sequence that is presented in the right col provided in the sequence listing.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Rejections - 35 USC § 112 - Indefiniteness
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.
Claim 72 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 72 is unclear over recitation of the phrase “the female target set of genes comprise” because there is no antecedent basis for any “female target set of genes” in either claim 72 or claim 19 from which claim 72 depends.
Claim Rejection - Improper Markush Group
Claims 5 and 72 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117(II).
Claims 5 and 72 each recite a alternative listing of genes identified by gene symbol, where the claims may include “one or more” (as recited in each of claim 5 and 72) of the recited genes. Applicants’ election is for the particular combination that is ZNF807 and LOC100130331.
The Markush group in each case is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 2117(II)).
Herein, the recited alternative species do not share a single structural similarity, as each gene has a different chemical structure in that it consists of a different nucleotide sequence which is required for is measurement and analysis. The only structural similarity present is that all of the genes comprise nucleotides. The fact that the genes comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides alone is not essential to the asserted common activity of having an expression level associated with ischemic cardiovascular disease, ischemic heart disease, coronary artery disease, cardiovascular congenital disease, hypertrophic or dilating cardiomyopathy, or heart failure. Accordingly, while the different genes are asserted to have the property of being correlated with vascular pathology, they do not share a substantial structural similarity essential to this activity.
Further, there is no expectation from the knowledge in the prior art that the different genes behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited genes possess the common property of being correlated with vascular pathology.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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 1, 5, 9, 11, 14, 19-20, 28, 70-72 and 76-77 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions including abstract ideas and natural phenomena without significantly more.
The claim(s) recite(s) a method including the detection gene expression levels of “a female targeted set of genes” or a “male targeted set of genes” (e.g.: as recited in claims 1, 5, 9, 28, 72), and gene expression level that is “indicative of” ischemic cardiovascular disease, ischemic heart disease, coronary artery disease, cardiovascular congenital disease, hypertrophic or dilating cardiomyopathy, or heart failure (as recited in claims 1 and 19). The claims further recite aspects of comparing gene expression levels between a sample and a control (e.g.: claims 9, 11, 28).
The claims are directed to an evaluation of data or information to reach a conclusion or make a judgment (identifying pathology based on some detected gene expression level), which is a mental process that is an abstract idea. The comparing of collected data clearly is directed to such a mental process that is an abstract idea (see MPEP 2106.04(a) III).
Additionally, where the claims recite aspects of genes being gender specific, or a correlation between biomarker expression and the presence of pathology, the claims are directed to the natural association between gene expression and pathology, and thus is directed to a natural phenomenon (see MPEP 2106.04(b) I).
This judicial exception is not integrated into a practical application because the claims do not practically apply the judicial exception(s), as noted above, 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 technical field;
An additional element that applies or uses 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; and
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.
Here it is noted that while the claims broadly recite a step of “providing a treatment” (i.e.: step (d) of claim 1; step (iii) of claim 19) “providing” is not a positive limitation because it does not require that the treatment actually be used by or on the patient (see MPEP 2106.04(d)(2).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because a step of measuring a gene expression level in a sample is well understood, routine and convention activity in the related prior art.
The teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available. For example, the specification (para 00219 on page 102 of the clean Substitute Specification of 06/28/2023) teaches that the RNA isolation of the claimed methods is well known in the art, and the gene expression analysis is performed using commercially available arrays from Affymetrix (page 90 of the clean Substitute Specification of 06/28/2023).
The prior art also demonstrates the well understood, routine, conventional nature of the additional elements because it teaches that the additional elements are well known or commercially available. For example, Kartalaei et al (2015) teaches whole-transcriptome analysis of hemogenic endothelial cells that express KDR. And Furuhata et al (2007) teaches gene expression analysis of EPCs. And Burgisser et al teaches gene expression microarray analysis of EPCs.
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112 – Written Description
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.
Claims 1, 5, 9, 11, 14, 19-20, 28, 70-72 and 76-77 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 methods of the rejected claims are directed to the detecting gene expression levels where the detected levels are indicative of having ischemic cardiovascular disease, ischemic heart disease, coronary artery disease, cardiovascular congenital disease, hypertrophic or dilating cardiomyopathy, or heart failure. However, the application as filed does not in fact disclose any particular levels (e.g.: an absolute amount of a transcripts such as ng/ml, or copies/ul; a relative amount such as a fold increase or decreased as compared to a level of a housekeeping gene or as compared to the expression level of the same gene in a subject with a known phenotype). The specification asserts that some genes can be used to detect the presence of pathology in a gender specific (i.e.: the genes of Table 1 are female specific target genes; the genes of Table 2 are male specific target genes) manner, but there is no teaching of what level of any particular gene is indicative of the presence of pathology.
Relevant to the breadth of the claims as they encompass gene expression levels found in any subject organism, while teaching only genes obtained from the analysis of human subjects, Hoshikawa et al (2003) teaches gene expression results among different organisms are different. The reference teaches the analysis of gene expression in lung tissue in response to hypoxic conditions which lead to pulmonary hypertension (Fig. 1), and provides that the gene expression profile in mouse is different from that observed in rat (Tables 1-4; p.209 - Abstract). Thus, the genes of the specification asserted to be associated with pathology in humans (as provide on p.89 of the Specification of 06/28/2023) is not a description of genes associated with pathology in any other subject organism (as encompassed by the claims in view of p.67 of the Specification of 06/28/2023).
Relevant to the claims as they encompass gene expression level in any sample (e.g.: as provide on p.164 of the Specification of 06/28/2023) while the specification teaches only an analysis of Flk1+ cells, it is relevant to point out the unpredictability with regard to the analysis of gene expression profiles obtained from different sample types. Cobb et al (2002) teaches the analysis of gene expression in spleen and liver samples from septic mice. Notably, the reference teaches that, when compared to a non-septic sample, the relevant expression profiles of the septic mouse spleen and the septic mouse liver contain different nucleic acids at different levels (Table 1; p.2714, middle col., lns.2-8). It is thus unpredictable as to how one might extrapolate gene expression levels from a urine sample (as provided in the instant specification) to a description of genes with pathology-associated expression in Flk1+ cells is not a description of such expression levels from any other sample type.
Furthermore, most of the claims are generic with regard to the structure of the genes of the methods, where the gene are only described by their functionality of being male or female-specific, and having some expression level associated with pathology. But the expression level of any gene that is associated with pathology is not something that is a prior evident from the gene itself; such an association must be established for any particular gene. Cheung et al (2003) teaches that there is natural variation in gene expression among different individuals and among different genes. Thus, the disclosure of some particular genes that may be associated with a pathology is not a description of any other different genes that may be associated with the pathology. And while the specification (p. 90 of the Specification of 06/28/2023) asserts that some machine learning identified genes associated with ischemia, there is no disclosure of any amounts of those genes that actually provide the identification of ischemia. Furthermore, where the claims encompass the analysis of as few as two genes, the specification teaches that more genes (8 gene for females; 12 gene for males) were required to accurately identify ischemia. An assertion that some correlation was found is not itself a description of the expression levels as required by the claims. This finding is also emphasized in Ex Parte Kubin (No. 2007-0819, Bd. Pat. App. & Int. May 31, 2007), wherein it is stated that:
“Although there is often significant overlap” between the enablement and written description requirements, “they are nonetheless independent of each other.” University of Rochester, 358 F.3d at 921, 69 USPQ2d at 1891. An “invention may be enabled even though it has not been described.” Id. Such is the situation here. While we conclude one skilled in the art would have been able to make and use the full scope of claim 73 through routine experimentation, we find Appellants did not describe the invention of claim 73 sufficiently to show they had possession of the claimed genus of nucleic acids. See, e.g., Noelle v. Lederman, 355 F.3d 1343, 1348, 69 USPQ2d 1508, 1513 (Fed. Cir. 2004) (“invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed”).
Thereby, a showing of how to potentially identify genes that might be used in the claimed methods is not sufficient to establish that Applicants were in possession of the invention as broadly claimed.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683