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 species: FPR1, CD63, FCGR2C, and DUSP16 in the reply filed on 9/25/2025 is acknowledged.
Claims 1-10 are pending and under consideration in this non final office action.
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 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method of diagnosing stroke using gene expression signatures, as well as distinguishing cardioembolic stroke from large artery atherosclerosis stroke. However this recitation is a natural correlation between expression levels of genes and stroke as well as stroke types. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also “diagnosing”, “distinguishing”, “differentiating”, “detecting”, “determine”, etc, however these steps are directed to the recitation of abstract ideas because they encompass conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims appear to recite steps of using gene expression signatures, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method. All of the steps of the method of claim 1, for example, are directed to gathering data.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, all of the steps and elements are recited at a high level of generality, and appear to be directed to gathering data from which to draw a conclusion. The generally recited steps and elements do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. Furthermore, the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
112(a)
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.
Claims 1-10 are rejected under 35 U.S.C. 112(a) 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, at the time the application was filed, had possession of the claimed invention.
Relevant to the lack of particular structural limitations in the rejected claims drawn to methods of using “gene expression signatures”, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
Additionally, at 2163IIA3(a), the MPEP states:
“…describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene “because it is only an indication of what the gene does, rather than what it is.”); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The claims are broadly drawn to methods of diagnosing stroke “using gene expression signatures”. It is noted that claim 1 does not define any structural requirements for these gene expression “signatures” while claims 5-8 recite a list of genes without setting forth how the genes are utilized in the method.
In the case of the instant claims, the functionality of identifying genes whose expression is diagnostic of stroke, differentiates cardioembolic stroke from large artery atherosclerosis stroke, and detects atrial fibrillation from cardioembolic stroke appears to be a critical feature of the claimed methods.
The specification discloses the following as guidance at paragraph 0060:
“The results and conclusions of the method of diagnosis are discussed as follows. This was a planned interim cohort study of the 1700 patients enrolled in the BASE trial that does not include lacunar strokes, cryptogenic strokes, TIA, or stroke mimics. Overall, 224 patients were enrolled with NIHSS>=5, 59 (26%) with LAS, 165 (74%) with CES, and 66 control subjects; 56% were male, and median (IQR) age was 72.9 years (63.7, 82.9). Median (IQR) time from symptom onset to blood collection was 487 (321, 1129) minutes. Coexistent pathology at presentation included atrial fibrillation 120 (54%), hypertension 186 (83%), hyperlipidemia 186 (48%), diabetes 74 (33%), and coronary artery disease 78 (35%). Patients were randomly divided into training (132) and validation (92). The diagnostic 12 gene signature results distinguished stroke from control; C-statistic 0.86, sensitivity of 0.91, specificity of .61. The diagnostic 3 gene signature results distinguished CES from LAA C-statistic 0.70, sensitivity of 0.85, specificity of 0.49. The diagnostic 8 gene signature results distinguished AF from (a) cardioembolic stroke not due to atrial fibrillation and (b) LAA, C-statistic 0.69, sensitivity of 0.70, specificity of 0.59.”
It appears, therefore, that all of the genes listed for each claim are required for each signature, since the specification states for example, “the diagnostic 3 gene signature results distinguished CES from LAA”. However, the specification does not teach whether the expression of any of the genes alone can be used for diagnosis or differentiation as required by the claims. Additionally, there does not appear to be any correlation between the structure of the genes identified for the 3 different signatures taught in the specification, and the phenotypes they are “diagnostic” of. Therefore, the skilled artisan would not be capable of distinguishing which genes, other than those recited, belong to the claimed genus, that is diagnostic of a) stroke, b) differentiate cardioembolic stroke from large artery atherosclerosis stroke, or c) detects atrial fibrillation from cardioembolic stroke, from those that are not diagnostic.
While the skilled artisan may be capable of performing gene expression analysis in patients suffering from different cardiovascular and stroke symptoms, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
The claims encompass a genus of structurally undefined genes whose expression must be capable of functioning as diagnostics for: a) stroke, b) differentiate cardioembolic stroke from large artery atherosclerosis stroke, or c) detects atrial fibrillation from cardioembolic stroke. However, the listed genes are not representative of the claimed genus because the skilled artisan would not be capable of distinguishing which additional gene sets are functionally diagnostic, as claimed, from genes that are not. For claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. Further, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“ [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Thus considering the structure of the individual genes, and the makeup of the particularly required “gene signatures” required by the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
112(b)
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 1-10 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.
Claim 1 recites a method for diagnosing stroke using gene expression signatures, however none of the active steps of the method set forth how to use the gene expression signatures. The distinguishing step is unclear because the claim does not recite how to perform the step. For example, is this step performed using gene expression or is it performed by a medical professional in a laboratory setting using stroke metabolite biomarkers in blood? Likewise, it is not clear if the differentiating step requires gene expression signature analysis or if it is diagnosed in a hospital using imaging and cardiac tests? Additionally, it is not clear if the detection of atrial fibrillation is a consequence of steps a and b, or if it is an added step of procuring the clinical history of the patient to determine if they suffer from atrial fibrillation. In the instant claims, the lack of clear method steps that relate back to the preamble renders the claim indefinite because the metes and bounds of what is required to perform the method is unclear. Without any steps in the body of the claim, the preamble appears to encompass merely reciting an intended use limitation without further limiting the actual active steps required to perform the claimed method. It is additionally noted that claim 10 is also indefinite for the same reasons. Again, the claim only recites a step of “utilizes” without clearly setting forth the active steps required by the claim.
Claim 2 is unclear in the recitation of “atrial fibrillation from cardioembolic stroke”. It is not clear if this recitation refers to atrial fibrillation caused by cardioembolic stroke or atrial fibrillation that is concurrent with cardioembolic stroke. This is made even more confusing in claims 3 and 8 with the recitation of “atrial fibrillation from cardioembolic stroke not due to atrial fibrillation and large artery atherosclerosis stroke”. This recitation is generally narrative such that the metes and bounds of what is being detected is unclear. It is not clear what type of atrial fibrillation is intended to be encompassed by the claim or what the relationship is between cardioembolic stroke or large artery atherosclerosis stroke and the atrial fibrillation being detected.
Claims 5-8 include a list of genes recited in the alternative, however none of these claims provide any guidance as to how the genes are comprised in signatures, and what data these signatures produce to be able to distinguish the phenotypes set forth in each of these dependent claims. Is a single gene and its expression level considered a “signature” or does a signature require a pattern of gene expression for a particular combination of genes? Additionally, claims 7 and 8 recite the same genes, however it is not clear if these genes are intended to be used to diagnose atrial fibrillation from cardioembolic stroke or can also be diagnostic of atrial fibrillation prior to stroke.
Claims 5-8 recite the phrase “selected from the group comprising” or “selected from a group comprising”. The claims appear to attempt to list a Markush group of alternatively usable embodiments, however, as set forth in the MPEP 2173.05(h), a Markush group is a closed group of alternatives, that is, the selection is made from the group “consisting” of, rather than “comprising”. The recitation of “selected from the [a] group comprising” is vague because it is unclear what other alternatives are intended to be encompassed by the claim.
Claim 9 depends from claim 1, but only recites “forms a two way random forest classifier through cross validation…”, however it is not clear what performs the action of “forms a two way random forest classifier…”. Is this formation a result of the steps of claim 1, does this step lack antecedent basis, or is it inherent to each of the steps in claim 1?
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.
Claims 1-8 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sharp (Sharp et al; US 2016/0265059; cited in the IDS filed 4/4/2023).
Sharp teaches using biomarker expression for stroke diagnosis (see abstract). With regard to claims 1-3, Sharp teaches distinguishing body fluid of stroke patients from normal patients (see paragraphs 0010-0014, 0046), Sharp teaches distinguishing cardioembolic stroke from large vessel ischemic stroke (para 0008), and Sharp teaches detecting atrial fibrillation (para 0055). With regard to claim 4, Sharp teaches the biological sample is selected from blood, serum, or plasma (para 0064). With regard to claims 5-8, and 10 Sharp teaches a group of biomarkers that comprise the claimed genes, including FCGR2C (para 0026, tables 9, 10, 13, 14, 15), and using panels of expression markers to determine occurrence of stroke, stratification of cardioembolic stroke, and atrial fibrillation.
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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Sharp in view of Baird (Baird et al; US 2016/0258019; cited in the IDS filed 4/4/2023).
The teachings of Sharp are set forth above and fully incorporated herein. Sharp does not teach the biomarker FPR1, however Baird teaches a number of transcripts that distinguished stroke patients from normal subjects (table 2), including FPR1. Therefore it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to having include genes taught by Baird in the method of diagnosis of Sharp for the obvious benefit of arriving at a comprehensive list of biomarkers that are diagnostic of stroke.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Sharp in view of Xing (Xing et al; Medical Science Monitor, vol 23, pages 9994-1000, 2017).
The teachings of Sharp are set forth above and fully incorporated herein. Sharp does not teach a two way random forest classifier through cross validation of training data resulting in distinct signatures, however Xing teaches using random forest classification with validation of training set data to calculate pathways in cardioembolic stroke (see abstract, methods). Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date to have used random forest classification in the method of Sharp to validate the data taught by Sharp for the purpose of distinguishing biological samples of stroke patients from normal controls as taught by both Sharp and Xing (page 1000).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Winston Shen, can be reached on (571) 272-3157. The fax phone number for organization where this application or proceeding is assigned is (571) 273-8300.
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/JEHANNE S SITTON/ Primary Examiner, Art Unit 1682