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 .
The claims dated 6/1/2026 are under consideration.
Election/Restrictions
Applicant's election with traverse of Group II, claims 1b, 2-5, 16-17, 31 and 34 in the reply filed on 6/1/2026 is acknowledged. The traversal is on the ground(s) that the claims relate to methods for classifying a subject into a sepsis mechanistic endotype selected from neutrophilic-suppressive (NPS), inflammatory (INF), innate host defense (IHD), interferon (IFN) and adaptive (ADA) endotypes, methods for treating sepsis in a subject classified as having such a sepsis endotype, kits for classifying a subject into a sepsis mechanistic endotype, and methods for identifying a candidate agent for the treatment of sepsis in a subject classified in having such a sepsis endotype and that claims 25-30 should be included in Group I and Group II in view of these claims being ultimately dependent from claim 1. This is not found persuasive because the active method steps of the claims of Group I and II do not require any step “classifying” a subject. Group III did not require any active method step of “classifying” and/or “predicting”. Group IV did not require any steps as it is a product. Group V did involve a step of “selecting” but none of the other groups require such a step. Group VI did not require any steps as it is a product.
Applicant is correct regarding claims 25-30. The claims are included with the election of group I. The claims for Group III is corrected to claims 22-23 and 36.
The requirement is still deemed proper and is therefore made FINAL.
Claims 3, 4, 5, 40 and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/1/2026.
Claims 3, 4 and 5 further limit claim 1a, which corresponds to Group I. The claims are withdrawn for this reason.
Priority
The present application is a 371 national stage entry of PCT/CA2022/050831 (filed 5/25/2022), which claims benefit to US provisional application 63/192,746 (filed 5/25/2021).
Priority is recognized.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited on a submitted IDS, they have not been considered.
Specification
The amendments to the specification are acknowledged.
Claim Objections
Claim 2 is objected to because of the following informalities: the claim references withdrawn subject matter, in particular “endotype sub-signatures”. Appropriate correction is required.
Claim Interpretation
Claim 1 is drawn to a “method for classifying a subject into a sepsis mechanistic endotype selected from neutrophilic-suppressive (NPS), inflammatory (INF), innate host defense (IHD), interferon (IFN) and adaptive (ADA) endotypes”; however, the active method steps do not explicitly require a step of “classifying” a subject in any manner. MPEP 2111.02 states:
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction.
Accordingly, the claim language of “method for classifying a subject into a sepsis mechanistic endotype selected from neutrophilic-suppressive (NPS), inflammatory (INF), innate host defense (IHD), interferon (IFN) and adaptive (ADA) endotypes” merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims. The claims are given the broadest reasonable interpretation as requiring:
(i) determining, in a biological sample from the subject, a level of expression for each of a plurality of genes, to provide a sample gene signature; and
(ii) comparing the sample gene signature with a reference gene signature to determine whether the subject has the sepsis mechanistic endotype, wherein the sample gene signature and reference gene signature comprise an NPS endotype signature pair, an INF endotype signature pair, an IHD endotype signature pair, an IFN endotype signature pair, an ADA endotype signature pair or combinations thereof.
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, 2, 16, 17, 25, 26, 27, 28, 29, 30, 31 and 34 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more.
The claim(s) recite(s):
“comparing the sample gene signature with a reference gene signature to determine whether the subject has the sepsis mechanistic endotype” (claim 1); and
“a difference between a sample endotype sub-signature or signature pair and a reference endotype sub- signature or signature pair indicates that the subject has the sepsis mechanistic endotype corresponding to that sub-signature or signature pair” (claim 2).
The “comparing” step broadly encompasses an abstract in that the step may carried out in a purely mental manner or with the aid of pen and paper. The step involves comparing four data points, 2 determined from the sample and 2 from the reference gene signature. This limited amount of data may be fully considered by the human mind.
The description of a “difference” in claim 2 sets forth a natural correlation between expression levels and the type of disease a patient has. Such a correlation is a judicial exception.
The judicial exceptions are not integrated into a practical application because the claims do not involve:
improvements to the functioning of a computer or to any other technology or technical field;
applying or using the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition;
applying the judicial exception with, or by use of, a particular machine; or
effecting a transformation or reduction of a particular article to a different state or thing.
The claimed limitations add insignificant extra-solution activity to the judicial exceptions as they are data gathering.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims encompass the use of methods of detecting and quantifying expression of genes that are well-known in the art as explicitly stated in paragraph 105 of the instant specification.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2, 16, 17, 25, 26, 27, 28, 29, 30, 31 and 34 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.
Regarding claim 1, it is not clear how the recited preamble is intended to breathe life and meaning into the claims. The preamble of the claim recites a “method for classifying a subject into a sepsis mechanistic endotype selected from neutrophilic-suppressive (NPS), inflammatory (INF), innate host defense (IHD), interferon (IFN) and adaptive (ADA) endotypes”. However, the method steps in the claim only require steps of “determining…a level of expression for each of a plurality of genes” and “comparing the sample gene signature”. Thus, it is unclear if applicant intends to cover any method of carrying out the two steps, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal of classifying a subject as set forth by the preamble of the claim. Amending the claim to include an active process step directed towards classifying the subject based on the determined expression levels may aid in overcoming this rejection.
Claims 2, 16, 17, 25, 26, 27, 28, 29, 30, 31 and 34 are similarly indefinite because they directly or indirectly depend from claim 1.
Regarding claim 1, the claim states the “determining” step is done “to provide a sample gene signature”. It is unclear if any additional elements are required in order to accomplish the recited result.
Claims 2, 16, 17, 25, 26, 27, 28, 29, 30, 31 and 34 are similarly indefinite because they directly or indirectly depend from claim 1.
Regarding claim 1, the claim states the “comparing” is done “to determine whether the subject has the sepsis mechanistic endotype”. It is unclear if any additional elements are required in order to accomplish the recited result.
Claims 2, 16, 17, 25, 26, 27, 28, 29, 30, 31 and 34 are similarly indefinite because they directly or indirectly depend from claim 1.
Regarding claim 31, the claim recites:
wherein the biological sample has been obtained from the subject prior to admission in an intensive care unit; and/or
wherein the biological sample has been obtained from the subject at first clinical presentation; or
wherein the biological sample has been obtained from the subject within the first day after entry into an intensive care unit.
It is unclear based on the use of the passive voice if the claim requires an active method step of “obtaining” the biological sample from the subject at at least one of the recited time points.
Regarding claim 34, the claim requires “classifying a subject…by a method of claim 1”. Claim 1 does not require “classifying” a subject as an active method step. Thus, claim 34 is incomplete as claim 1 does not specifically result in or accomplish the goal of “classifying a subject”.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 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.
Claim(s) 1, 2, 16, 17, 25, 26, 29, 30, 31 and 34 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dickinson (Genomics Data. 2015. 3:41-48) as evidenced by Ensembl (retrieved on 7/1/2026 from the internet: useast.ensembl.org).
Regarding claims 1, 16, 17, 26, 29 and 30, Dickinson teaches determining the expression of a plurality of genes in a blood sample (p. 42, Sample collection and RNA extraction) using the Affymetrix HG-U133 plus 2.0 array (p. 45, RNA labeling and hybridization).
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The Affymetrix HG-U133 plus 2.0 array includes probes for: IFI27 and LGALS3BP; MAP7 and SPRED1; ETV7 and PLEKHO1; FECH and TFEC; GADD45A and EFNA1, as evidence by Ensembl and as represented below:
Dickinson further teaches comparing the expression levels between the blood sample of infected subjects as a “sample gene signature” and controls as a “reference gene signature” (p. 47, Statistical analysis).
Dickinson anticipates the claims because it teaches all the positively active method steps of the claim in view of the broadest reasonable interpretation provided above.
Regarding claim 2, Dickinson teaches controls as a “reference gene signature” which represents the standard level of expression of the genes in healthy subjects (Fig. 1).
Regarding claim 25, Dickinson teaches using the Affymetrix HG-U133 plus 2.0 array as noted above. The array detects expression of nucleic acids encoded by the genes.
Regarding claim 31, Dickinson teaches the blood samples are from subject after clinical presentation of early symptoms (p. 42, Patient demographics and experimental design).
Regarding claim 34, Dickinson teaches the elements of claim 1 as described above. Dickinson further teaches patients were given antibiotics (Table 2).
Claim(s) 1, 2, 25, 26, 29 and 30 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Leite (npj Systems Biology and Applications. 2019. 5:26).
Regarding claim 1, 25, 26, 29 and 30, Leite teaches determining the expression of CA1 and GYPA (Tables 2, 3 and 4) in blood samples (Table 1), as encompassed by an INF endotype signature pair, using arrays (Table 1).
Leite further teaches comparing the expression levels between the blood sample of patients as a “sample gene signature” and controls as a “reference gene signature” (p. 6, Microarray datasets selection and data analysis).
Leite anticipates the claims because it teaches all the positively active method steps of the claim in view of the broadest reasonable interpretation provided above.
Regarding claim 2, Leite teaches controls as a “reference gene signature” which represents the standard level of expression of the genes in healthy subjects.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 27 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dickinson (Genomics Data. 2015. 3:41-48) as evidenced by Ensembl (retrieved on 7/1/2026 from the internet: useast.ensembl.org) in view of Griffiths (US 2018/0312907 A1).
Regarding claims 27 and 28, Dickinson teaches determining the expression of a plurality of genes in a blood sample (p. 42, Sample collection and RNA extraction) using the Affymetrix HG-U133 plus 2.0 array (p. 45, RNA labeling and hybridization).
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The Affymetrix HG-U133 plus 2.0 array includes probes for: IFI27 and LGALS3BP; MAP7 and SPRED1; ETV7 and PLEKHO1; FECH and TFEC; GADD45A and EFNA1, as evidence by Ensembl and as represented below:
Dickinson further teaches comparing the expression levels between the blood sample of infected subjects as a “sample gene signature” and controls as a “reference gene signature” (p. 47, Statistical analysis).
Dickinson does not specifically teach determining the expression of genes using the particular methodologies of claims 27 and 28.
However, Griffiths teaches gene expression can be measured directly by techniques that allow the detection and quantification of RNA target molecules, such as RT-PCR, real-time PCR, Northern blot, RNA sequencing (RNA-seq) and RNA microarray (para. 83) in the context of bacterial infections such as sepsis (para. 50).
It would have been prima facie obvious to the ordinary artisan at the time of filing that the arrays of Dickinson may be substituted with PCR assays or RNA-seq. Griffiths demonstrates that each were know and are obvious variants of one another for the purpose of analyzing gene expression. For example, one may choose RNA-seq because it provides additional information regarding mRNA levels, miRNA levels and/or lncRNA levels or one may choose PCR as it is an extremely conventional assay.
Claim(s) 27 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Leite (npj Systems Biology and Applications. 2019. 5:26) in view of Griffiths (US 2018/0312907 A1).
Regarding claims 27 and 28, Leite teaches determining the expression of CA1 and GYPA (Tables 2, 3 and 4) in blood samples (Table 1), as encompassed by an INF endotype signature pair, using arrays (Table 1).
Leite further teaches comparing the expression levels between the blood sample of patients as a “sample gene signature” and controls as a “reference gene signature” (p. 6, Microarray datasets selection and data analysis).
Leite does not specifically teach determining the expression of genes using the particular methodologies of claims 27 and 28.
However, Griffiths teaches gene expression can be measured directly by techniques that allow the detection and quantification of RNA target molecules, such as RT-PCR, real-time PCR, Northern blot, RNA sequencing (RNA-seq) and RNA microarray (para. 83) in the context of bacterial infections such as sepsis (para. 50).
It would have been prima facie obvious to the ordinary artisan at the time of filing that the arrays of Leite may be substituted with PCR assays or RNA-seq. Griffiths demonstrates that each were know and are obvious variants of one another for the purpose of analyzing gene expression. For example, one may choose RNA-seq because it provides additional information regarding mRNA levels, miRNA levels and/or lncRNA levels or one may choose PCR as it is an extremely conventional assay.
Improper Markush Group
Claims 1, 2, 16, 17, 25, 26, 27, 28, 29, 30, 31 and 34 are rejected on the basis that they contain 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 § 706.03(y).
The claims recite the following Markush grouping: the various gene pairs included in the five endotypes. The Markush group 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 706.03(y) 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 706.03(y)IIA).
Here, 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 and encodes a protein with a different structure and function. The only structural similarity present is that all of the genes comprise nucleotides or all the proteins comprise amino acid. The fact that the genes comprise nucleotides or proteins comprise amino acids per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides or amino acids alone is not essential to the asserted common activity of being correlated with an endotype. Accordingly, while the different genes are asserted to have the property of being correlated with endotypes, they do not share a substantial structural similarity essential to this activity.
Further, the recited genes do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that 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 different endotypes.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH G. DAUNER/Primary Examiner, Art Unit 1682
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