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 .
This Office Action is in reply to Applicants’ correspondence of 06/04/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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among the particular markers recited as Flk-1, KDR, VEGFR2, or CD309 (see page 4 of the Requirement of 07/29/2025) is withdrawn.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LOC100130331; i.e.: LOC100130331 does not appear among the particular female specific genes of Tables 1, 3 and 5) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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.
Withdrawn Notification of Deficiencies
Nucleotide and/or Amino Acid Sequence Disclosures
The notification of deficiencies related to nucleotide and/or amino acid sequences disclosures, as set forth on pages 3-6 of the Office Action of 02/04/2026, are withdrawn in light of the amendments to the specification.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejection of claims made under 35 USC 112(b) as set forth on page 6 of the Office Action of 02/04/2026 is withdrawn in light of the amendments to the claims.
New Claim Rejections - 35 USC § 112 – Indefiniteness
Necessitated by Claim Amendments
Claims 1, 5, 9, 11, 14, 19-20, 28, 70-72 and 76-77 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, 5, 9, 11, 14, 70 and 71 are unclear over recitation of the phrase “the condition” as recited in line 6 of claim 1 from which claims 5, 9, 11, 14, 70 and 71 depend. There is no antecedent basis in the claim 1 for any condition (e.g.: recitation of any particular conditions prior to recitation of the unclear limitation).
Claim 19, 20, 28, 72, 76 and 77 are unclear over recitation of the phrase “the condition” as recited in line 9 of claim 19 from which claims 20, 28, 72, 76 and 77 depend. There is no antecedent basis in the claim 19 for any condition (e.g.: recitation of any particular conditions prior to recitation of the unclear limitation).
Maintained 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.
Response to Remarks
Applicants have traversed the rejection of claims as directed to an improper Markush style grouping of alternative useable elements. Applicants’ arguments (p.12-14 of the Remarks of 06/04/2026) have been considered but are not persuasive to withdrawn the rejection. Applicants have argued that the different genes recited in claims 5 and 72 share both a single structural similarity and a common use.
Applicants have initially argued that the different genes are all members of an art recognized class that the “genes whose expression levels are differentially expressed in hematopoietic endothelial precursor cells (EPCs) of female subjects with ischemic cardiovascular conditions as compared to control subjects”. Applicants point to the disclosure of the specification as evidence that the different gene have differential expression in KDR1+ EPCs derived from female subjects. But the argument is not persuasive because it point to the asserted novel findings of the application, not to any evidence that “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”.
Applicants further argue that the different genes have a “common use” in the detection of variable gene expression related to cardiovascular conditions. This argument is not persuasive because the asserted common use does not flow from any substantial structural feature that is shared among the different genes (e.g.: see MPEP 2117(II)(B) ). The examiner maintains that the common use is derived from the biological activity of each individual protein encoded by each individual gene, where the biological activity is afforded to each protein from its unique structure and amino acid sequence. The different genes (and their encoded proteins) do not share some substantial structural feature that provides a common use of being associated with cardiovascular conditions in a subject.
Applicants finally argue that “these genes share the substantial structural feature of being differentially expressed in hematopoietic EPCs under ischemic conditions in female subjects”. This argument is not persuasive because this argued feature is not a “structural feature”, but is a non-structural property of the genes that is analogous to their use in the claimed methods (differential expression identifies ischemic conditions). But this shared use can not be properly considered a structural element or structural component that is shared among the different genes; there is no, for example, amino acid sequence that is shared among the different encoded proteins of the different genes which can be moved to a different gene which would then convey to that different gene a differential expression in the presence on ischemic conditions.
Maintained Claim Rejections - 35 USC § 101
Modified as Necessitated by Claim Amendments
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.: recited in claims 1 and 19).
The claims are directed to an evaluation of data or information to reach a conclusion or make a judgment (e.g.: encompassing the identification of a pathology based on some compared gene expression level), which is a mental process that is an abstract idea. The comparing of collected data clearly is directed to a mental process and thus 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 compared biomarker expression and the presence of pathology, the claims are directed to the natural association between gene expression and pathology, and thus the claims are directed to a natural phenomenon (see MPEP 2106.04(b) I).
This judicial exception is not integrated into a practical application. Here it is noted that while the amended claims recite a step of “administering to the subject a treatment selected from the group consisting of beta-blockers, calcium channels antagonists, nitrates, aspirin, cholesterol-lowering compounds, angiotensin converting enzyme (ACE) inhibitors, and ranolazine” (i.e.: step (d) of claim 1; step (iii) of claim 19) the administering is applied to all subjects of the claimed methods. The claims recite steps of collecting gene expression levels, and comparing the levels of control levels. The claims recite an asserted inherent property of the compared gene expression levels (see for example step (b) of claim 1), such as:
wherein expression levels from (b) outside a range of the control expression levels are indicative of the female subject's having a condition selected from ischemic cardiovascular disease, ischemic heart disease, coronary artery disease, cardiovascular congenital disease, hypertrophic or dilating cardiomyopathy, heart failure
But this recited “wherein” clause is not a requirement that, in the practice of the claimed methods, “expression levels … outside a range of the control expression levels” are in fact present and detected. As such the claims are directed to the treatment of all subjects, regardless of whether or not an expression level that is diagnostic of the recited conditions is present. Because the recited treatment is administered regardless of condition status, this administration is not an integration of the judicial exception. The claims do not specify which subjects are treated, direct the methods to the treating of a specific patient population based upon their gene expression profile. Thus, the claim is directed to a judicial exception.
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.
Response to Remarks
Applicants have traversed the rejection of claims made under 35 USC 101 as directed to a judicial exception to patentability without significantly more. Applicants’ arguments (p.14-15 of the Remarks of 06/04/2026) have been considered but are not persuasive to withdrawn the rejection.
Applicants have argued that the amended claims integrate any judicial exception into a practical application because the claims apply the diagnostic information to effect a particular treatment for the identified cardiovascular conditions, and that the claims as amended are directed to methods of treating patients diagnosed with cardiovascular conditions, where the diagnostic gene expression analysis informs the treatment decision, and the treatment is then actively administered to the patient. The arguments are not persuasive because the claims lack any required step of diagnosing the subject as having cardiovascular conditions. As noted in the rejection, while the claims recite a wherein clause that asserts a relationship between a compared gene expression level and an indication of having a condition selected from ischemic cardiovascular disease, ischemic heart disease, coronary artery disease, cardiovascular congenital disease, hypertrophic or dilating cardiomyopathy, heart failure, the recitation of this assertion association is not the same as a requirement that the compared level is in fact present and detected in a sample form the subject. Thus, the claims are directed to the treatment of all subject form which a sample is analyzed, regardless of whether or not the indicative gene expression level is present in the sample. The argument that the claim structure of diagnosis followed by treatment administration represents a practical application of any underlying natural phenomenon or abstract idea because the claims require a specific therapeutic intervention based on the diagnostic output is not persuasive because there is no specific diagnostic output required by the claims.
Maintained Claim Rejections - 35 USC § 112 – Written Description
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 as compared to control expression levels are indicative of having ischemic cardiovascular disease, ischemic heart disease, coronary artery disease, cardiovascular congenital disease, hypertrophic or dilating cardiomyopathy, or heart failure.
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 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 any other different sample type; 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.
Response to Remarks
Applicants have traversed the rejection of claims made under 35 USC 112 as directed to subject matter that is not adequately described by the originally filed application. Applicants’ arguments (p.15-18 of the Remarks of 06/04/2026) have been considered but are not persuasive to withdrawn the rejection.
Applicants have first argued that the claims are amended to include a step of comparing an expression level form a sample to control expression levels. In this regard it is noted that the rejection as it was previously applied to the claims encompassing any method of assaying for a gene expression level is not maintained in the rejection as set forth above.
Applicants have next argued that the practical scope of the claim is the methods as they are applied to humans, because the claims recite conditions and treatments that apply to human subjects, and genes recited using human gene symbols. This argument is not persuasive. Initially it is noted that the animal models such as chimpanzee (Pan troglodytes) serves as a spontaneous natural model for human-like cardiac aging and heart failure. As such the argument that the pathologies and treatments of the claims are human specific is not persuasive. Furthermore, with regard to the argument directed to the claims as they recite human gene symbols it is noted that most of the claims are generic with regard to what genes are analyzed with regard to their gene expression levels. Furthermore, it is noted that the gene symbol notation in the claims (i.e.: all capital letters) is not limited to humans, but is also used to indicate non-human primates as well as chicken genes.
Applicants have next argued that dependent claim 14 and independent claim 19 are directed to sample types that are EPCs, and that the specification asserts that any sample of body fluids or tissues is relevant to the claimed methods. In this regard the Examiner maintains that the application as filed only exemplifies the detection of gene expression of specific genes in Flk1+ EPCs as associated with pathology, and that such a teaching would not be understood by the skilled artisan to be readily extrapolated to the analysis of gene expression in any other sample type. The citation of Cobb et al in the rejection provides an example of the general understanding in the related art that different tissues in the same pathology may have distinct gene expression profiles. As such where the claims encompass methods which generically encompass any sample type, the rejection is maintained.
Applicants have next argued that the claims require analysis of specifically defined gene sets, and that the specification discloses specific genes that were identified through transcriptomic analysis of symptomatic patients. The argument is not persuasive because most of the claims do not in fact define the genes of methods; for example, claim 1 is directed to the analysis of any “female targeted set of genes”, and while the claims recites a functional association with ischemic conditions, there is a gap between the encompassed structures (e.g.: any gene in the genome of a female) and the required functionality (i.e.: associated with pathology). While the specification as filed provides several particular genes asserted to meet the functional limitations in some embodiments (i.e.: analysis of human Flk1+ EPCs), the teachings of the application do not allow the skilled artisan to select from the broadly encompassed genus any other genes that may provide the same functionality.
Applicants have finally argued that the specification provides that a classifier of only two biomarkers has an accuracy of 82%. But this argument is not persuasive to with the rejection as it is maintained with regard to the pending claim because most of the claims are not directed to any particular markers or genes used in a classifier. While the specification may provide a description of a particular embodiment encompassed by the claims, the particular examples of the application as filed do not demonstrate that applicants were in possession of the methods broadly encompassed by the rejected claims.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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
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