DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Herein, “the previous Office action” refers to the Final Rejection filed 4/9/2025.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/9/2025 has been entered.
Priority
As detailed on the Filing Receipt filed 7/11/2024, the instant application claims priority to as early as 11/15/2018. At this point in prosecution, all claims are accorded the earliest claimed priority date.
Information Disclosure Statement
The Information Disclosure Statement filed on 9/9/2025 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of the IDS is included with this Office Action.
Claim Status
Claims 2-3, 6, 12, 14-16 and 18-20 are canceled.
Claims 1, 4-5, 7-11, 13 and 17 are pending, and under examination.
Withdrawn Objections/Rejections
The rejection of claims 6, 12 and 19 under 35 USC § 112(b), as being indefinite, is hereby withdrawn in view of Applicant’s cancelation of the claims.
The rejection of claim 19 under 35 USC § 112(d), as being of improper dependent form, is hereby withdrawn in view of Applicant’s cancelation of the claim.
The rejection of claims 6 and 19 under 35 USC § 101, as being directed to nonstatutory subject matter, is hereby withdrawn in view of Applicant’s cancelation of the claim.
The rejection of claim 19 under 35 USC § 103, as being unpatentable over Liew, in view of Sasso, is hereby withdrawn in view of Applicant’s cancelation of the claim.
The rejection of claims 6 and 12 under 35 USC § 103, as being unpatentable over Liew, in view of Sasso and Quinn, is hereby withdrawn in view of Applicant’s cancelation of the claims.
The provisional rejection of claim 6 on grounds of nonstatutory double patenting, as being unpatentable over claims of Application No. 18/752,362, in view of Liew and Sasso, is hereby withdrawn in view of Applicant’s cancelation of the claim.
The provisional rejection of claims 6, 12 and 19 on grounds of nonstatutory double patenting, as being unpatentable over claims of Application No. 18/806,109, in view of Liew, is hereby withdrawn in view of Applicant’s cancelation of the claims.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art (MPEP 2111.01). This section documents the examiner’s interpretation of certain recited claim language.
Claim 1 recites the limitation of "the treatment is adjusted as a function of gene expression data" (pg. 213). Prior claim language does not recite an active treatment step. In the context of prior claim language, this limitation is interpreted as requiring that a user adjust the specification of treatment in the report (i.e., modify information).
Claim 17 recites the limitation of “wherein the report comprises different formats” (pg. 214). The specification describes embodiments wherein “the first records and the second records”, i.e., processed data, “are in different formats” (pg. 2, para. 0004) and “the report comprises different formats” (pg. 47, para. 0139), but does not specially define the term “different formats”. This term is interpreted broadly, as signifying “presentation of information in different forms or layouts”.
Claim Objections
Claim 1 is objected to because of the following informalities:
The lowercase letters respectively indicating steps of “performing an RNA-Seq analysis”(line 6) and “performing quantitative polymerase chain reaction” (line 9) should be amended from “(b)” and “(c)” to “(a)” and “(b)”.
Appropriate correction is required.
Response to Arguments - Claim Rejections Under 35 USC § 112
In the Remarks filed 9/9/2025, Applicant traverses the rejections under 35 USC § 112 and presents supporting arguments.
Applicant alleges that one of ordinary skill in the art would understand what is claimed by use of the term “gene module” in view of the specification (pg. 216, para. 6 – pg. 217, para. 1).
The Examiner agrees that the scope of the term “gene module”, as recited in the claims, would be understood by one of ordinary skill in the art as referring to a group of co-expressed genes and/or genes with similar expression profiles. However, it is unclear that one of ordinary skill in the art would understand the scope of the recited “genes of one or more gene modules of Table 1, 2… and 74” (claim 1, pg. 3). Determining the scope of the recited language would require one of ordinary skill in the art to understand the particular gene membership of the modules indicated by each listed Table.
One of ordinary skill in the art would understand the particular gene membership of modules indicated by certain of the listed Tables. For example, as noted by Applicant, Table 1 lists particular named modules (e.g., floralwhite) while Table 8 lists particular genes in each of these same modules. In consideration of Table 8, one of ordinary skill in the art would be apprised of the scope of “genes of one or more gene modules of Table 1”. However, to determine the full scope of the language as written, one of ordinary skill in the art would need to be apprised of the particular gene membership of every module indicated by every Table listed therein (i.e., Tables 1-2, 7-9, 13-16, 30, 32-34, 43A-43B, 49B, 71A-71B, 72B-72C and 74). The membership of every module is not clear from the specification. See rejection for further details. Therefore, the argument of definite scope in light of the specification is found unpersuasive.
Applicant notes amendment of claim 1 responsive to indication that the prior-recited limitation of “at an accuracy of at least 70%” was of uncertain scope (pg. 217, para. 3). Applicant’s amendment has removed the language at issue from its previous locations in the claims, and imported it elsewhere. The new location of this language clarifies its limitation of the recited use of a trained machine learning classifier, and is interpreted as requiring that utilized classifier has exhibited an accuracy (i.e., a performance metric) of at least 70% in classifying data (e.g., training data). The Examiner agrees that the particular association of this limitation with the use of a trained machine classifier has rendered it as definite. Nonetheless, the claim at large remains indefinite for the reasons explained regarding particular membership of recited gene modules.
Thus, the rejection is maintained with respect to the pending claims. Uncertainty regarding scope of the limitation of “at an accuracy of at least 70%” is considered resolved by Applicant’s amendment, and has been removed from the rejection.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 USC § 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, 4-5, 7-11, 13 and 17 are rejected under 35 USC § 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. This rejection is maintained from the previous Office action, and has been revised to address the amended claims (filed 3/17/2025).
With respect to claim 1 and dependents thereof, there is uncertainty regarding scope of the recited limitation of “genes of one or more gene modules of Table 1, 2… and 74” (pg. 3). Definite claims must apprise one of ordinary skill in the art of their scope, and thus provide clear warning to others as to what constitutes infringement of the patent (MPEP 2173.02). Determining the scope of the recited language would require one of ordinary skill in the art to understand the particular genes encompassed by (i.e., the particular membership of) the modules indicated by each listed Table. It is not clear that one of ordinary skill in the art would understand what is claimed, when the claims are read in light of the specification.
For example, Tables 1 and 7 list modules including ‘Pink’, ‘Purple’ and ‘Yellow’ in association with the cell type of ‘CD14’, and ‘Brown’ in association with ‘CD19’. Table 2 lists modules named ‘CD14_Pink, ‘CD14_Purple’, ‘CD14_Yellow’, and ‘CD19_Brown’. Table 8 lists sets of particular genes in cell type-associated modules named as in Table 1 (e.g., ‘Pink’ in association with ‘CD14’). One of ordinary skill in the art would reasonably conclude that the same particular gene modules are referenced in Tables 1-2 and 7-8, and be thereby apprised of the particular gene membership of each module via Table 8.
However, Tables 13-15 list modules including ‘pink’ in association with T cells, ‘purple’ in association with platelets, ‘yellow’ in association with ‘CD14’ and additional descriptors, ‘brown’ in association with inflammatory myeloid cells, as well as ‘light cyan’ and other uniquely-named modules. It is unclear if the ‘pink’, ‘purple’, ‘yellow’ and ‘brown’ modules of Tables 13-15 are the same as the ‘Pink’, ‘Purple’, ‘Yellow’ and ‘Brown’ modules of Tables 1-2 and 7-8, given their matching color names but differing listed cellular associations. The caption of Table 2 describes its contents as “[c]ell-specific modules”, suggesting that module identity is variable between cell types.
This uncertainty is worsened by review of further Tables. Table 49B indicates that a ‘Glomerulus module’ includes a ‘Brown’ microarray module that has given correspondence with a ‘Brown’ RNA-Seq module, which is associated with cell types including platelets. Table 49B further indicates that a ‘Tubulointerstitium module’ also includes a ‘Brown’ microarray module that has given correspondence with a ‘Black’ RNA-Seq module, which is associated with cell types including monocytes (pg. 457, Table 49B).
The correspondence of modules named in Tables 13-15 and 49B with those similarly-named in Tables 1-2 and 7-8 is uncertain. It is therefore uncertain whether, e.g., the particular genes listed for the ‘CD19_Brown’ module in Table 8 are also the particular genes encompassed by the ‘brown’ module in Tables 13-15 or the ‘Brown’ modules in Table 49B. Furthermore, certain modules (e.g., the ‘light cyan’ module of Tables 13-15) appear in Tables of the recited list but similar module names do not appear in any Tables (e.g., Table 8) which indicate particular gene membership. The membership of these unique modules is therefore unclear.
Thus, it is unclear that one of ordinary skill in the art would be apprised of the particular genes encompassed by each of the gene modules listed in each of the recited Tables. The full scope of the cited limitation is therefore indefinite. The examiner suggests extraction of particular desired table elements (e.g., sets of genes) from one or more tables and incorporation into the claims.
Certain tables of those recited list particular genes encompassed by given modules, including the noted Table 8 as well as Tables 30, 32, 43A-43B, 71A-71B and 72B-72C. Hence, the particular gene membership of the modules referenced therein is unambiguous. For purposes of prosecution, the recited limitation is noted as unambiguously encompassing genes of one or more gene modules of Tables 8, 30, 32, 43A-43B, 71A-71B and 72B-72C.
Additionally, there is uncertainty regarding scope of the recited limitation of “at an accuracy of at least 70%” (pg. 2). It is unclear from claim language how the claimed method must be performed to achieve results with any specific level of accuracy. The claims thereby recite a result achieved by the invention without reciting the particular structure, materials or steps that achieve the result (see MPEP 2173.05(g)).
For the above reasons, the claims are indefinite.
Response to Arguments - Claim Rejections Under 35 USC § 101
In the Remarks filed 9/9/2025, Applicant traverses the rejection under 35 USC § 101 and presents supporting arguments.
Applicant notes incorporation to claim 1 of limitations of now-canceled claim 12, which the previous Office action indicated as reciting statutory subject matter. Claim 11 was indicated therein as reciting statutory subject matter due in particular to its recital of an active administration step (“wherein the drug is administered to the subject”), while now-canceled claim 12 was likewise indicated as reciting statutory subject matter by virtue of its dependency on claim 11 (and accordant incorporation of the active administration step). Amended claim 1 recites the unique limitations of claim 12 (“wherein administration of the drug comprises parenteral administration of the drug to the subject”), but does not recite the active administration step that rendered claim 12, by virtue of dependency, as statutory.
The incorporation of certain limitations of now-canceled claim 12 to the independent claim is therefore not considered persuasive regarding statutory nature of the independent claim, and the rejection is maintained with respect to the pending claims.
Claim Rejections - 35 USC § 101
35 USC § 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, 4-5, 7-10, 13 and 17 are rejected under 35 USC § 101 because the claimed invention is directed to an abstract idea and natural phenomenon without significantly more, i.e., non-statutory subject matter. This rejection is maintained from the previous Office action, and has been revised to address the amended claims (filed 9/9/2025).
"Claims directed to nothing more than abstract ideas, natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I).
Abstract ideas include mathematical concepts (including formulas, equations and calculations), and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)).
Laws of nature and natural phenomena include principles, relations, and products that are naturally occurring or do not have markedly different characteristics compared to what occurs in nature (MPEP 2106.04(b)).
These claims as a whole, considering all claim elements both individually and in combination, do not amount to significantly more than an abstract idea and a natural phenomenon.
Step 1: The Four Categories of Statutory Subject Matter (MPEP 2106.03)
Claims 1, 4-5, 7-10, 13 and 17 (hereafter “the claims”) are directed to a method, which falls under the ‘process’ category of statutory subject matter.
Step 2A, Prong One: Whether the Claims Set Forth or Describe a Judicial Exception (MPEP 2106.04 § II.A.1)
‘Mathematical concepts’ are relationships between variables and numbers, numerical formulas or equations, or acts of calculation, which need not be expressed in mathematical symbols (MPEP 2106.04(a)(2) § I). The claims recite elements which encompass mathematical concepts, at least under their broadest reasonable interpretation, including:
“a trained machine learning classifier is used to analyze or process the data set to identify the state of the subject” (claim 1), i.e., an optimized classification algorithm is evaluated for input data to output a classification.
The recited acts of calculation constitute mathematical concepts.
‘Mental processes’ are processes that can be performed in the human mind at least with use of a physical aid, e.g., a slide rule or pen and paper (MPEP 2106.04(a)(2) § III). The claims recite elements that encompass processes that are practicably performable in the human mind, at least under their broadest reasonable interpretation, including:
“identifying and comparing (i) the gene expression data generated from assaying… to (ii) a reference gene expression data set comprising a plurality of gene signatures” (claim 1), i.e., comparing sets of information.
The recited steps are practicably performable in the human mind, and thus constitute mental processes.
The following claim elements delimit embodiments of the above mental processes, but do not alter their characterization as mental processes:
“the plurality of gene signatures comprises transcripts of genes of one or more gene modules of Table 1, 2… and 74” (claim 1);
Mathematical concepts and mental processes constitute enumerated groupings of abstract ideas (MPEP 2106.04(a)(2) §§ I and III). Hence, the claims recite elements that, individually and in combination, constitute an abstract idea.
Additionally, the claimed method comprises assaying a biological subject sample to generate gene expression data, and analyzing said data to output a report which identifies an immunological state, disease state, likelihood of treatment response, and/or effectiveness of treatment for the subject. These identifications are based on the analytical comparison of the generated gene expression data with reference data comprising a plurality of relevant gene signatures. Thus, the output identifications rely on natural correlations between a) features of subject-derived gene expression data for the plurality of gene signatures (e.g., presence of particular alleles) and b) subject immunological state, disease state or susceptibility thereof, likelihood of treatment response, and effectiveness of treatment. Hence, the claims recite elements that, individually and in combination, constitute a natural phenomenon.
The claims must therefore be examined further to determine whether they integrate these judicial exceptions into a practical application (MPEP 2106.04(d)).
Step 2A, Prong Two: Whether the Claims Contain Additional Elements that Integrate the Judicial Exception(s) into a Practical Application (MPEP 2106.04 § II.A.2)
The claims recite the following additional elements, which gather data necessary for performance of claimed method steps: “assaying an isolated biological sample from a subject to generate… gene expression data… comprising: performing an RNA-seq analysis… or… performing quantitative polymerase chain reaction (qPCR)”, wherein “the isolated biological sample is selected from a group consisting of: a whole blood (WB) sample, a peripheral blood mononuclear cell (PBMC) sample, a tissue sample, and a purified cell sample” (claim 1).
Necessary data gathering is considered to be insignificant pre-solution activity, and as such insufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)).
The claims further recite the following additional element, which outputs results of prior method steps: “electronically outputting a report detailing the comparison” (claim 1).
Data output is considered insignificant post-solution activity, and as such insufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)).
Further claim elements require that the report comprise information pertaining to particular concepts (e.g., disease states, forms of treatment) and having particular form, including:
“the report… identifies an immunological state of the subject… a disease state or a susceptibility thereof of the subject… if the subject is likely to respond to treatment comprising administration of a drug selected from: an immunoregulator, an immunosuppressant…an anti-CD28 biologic, or combinations thereof… and/or… an effectiveness of the treatment of the subject as compared to the disease state or disease progression” (claim 1), wherein:
“the disease state is associated to the plurality of gene signatures” (claim 1),
“the treatment is adjusted as a function of gene expression data” (claim 1, see ‘Claim Interpretation’ section);
“the disease state is selected from: a chronic condition, an inflammatory condition… an inflammatory arthritis, or combinations thereof” (claim 1);
“the disease state is the arthritis” (claim 4);
“the disease state is the rheumatoid arthritis” (claim 5);
“the disease state is the inflammatory arthritis” (claim 7);
“the disease state is the chronic condition” (claim 8);
“the disease state is the inflammatory condition” (claim 9);
“the disease state is the autoimmune condition” (claim 10);
“the treatment comprises administration for about one week to about: 16 weeks… or the subject lifespan” (claim 13); and
“the report comprises different formats” (claim 17).
The recited identifications rely on performance of the prior analysis, and their presence on the report does not alter the nature of outputting the report as mere data output. Neither do the identities of the disease state, treatment or phenotype to which the report pertains, or the sources of data represented therein, alter the nature of the outputting step as mere data output. See MPEP guidance regarding printed matter (MPEP 2111.05).
These elements merely link the judicial exceptions to particular fields of use (e.g., rheumatic disease therapy). Field-of-use limitations are insufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(h)).
The recited term “electronically” (in “electronically outputting”) further requires performance of the outputting step using a computer. The claims further recite the following additional element, which similarly requires performance of claimed functions using a computer: “using a computer comprising a non-transitory computer-readable storage medium encoded with a computer program including instructions executable by a processor to run an application for” (claim 1) performance of method functions.
The claims do not describe any specific computational steps by which a computer performs or carries out functions drawn to the judicial exceptions, nor do they provide any details of how specific structures of a computer are used to implement these functions. The claims state nothing more than that a computer performs functions drawn to the judicial exceptions, and therefore recite mere instructions to apply the judicial exceptions using a generic computer. Such instructions are insufficient to integrate the judicial exceptions into a practical application (see MPEP 2106.04(d) § I and 2106.05(f)).
No further additional elements are recited.
When the claims are considered as a whole: they do not improve the functioning of a computer, other technology, or technical field (MPEP 2106.04(d)(1) and 2106.05(a)); they do not apply the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition (MPEP 2106.04(d)(2)); they do not implement the judicial exceptions with, or in conjunction with, a particular machine (MPEP 2106.05(b)); they do not effect a transformation or reduction of a particular article to a different state or thing (MPEP 2106.05(c)); and they do not apply or use the judicial exceptions in some other meaningful way beyond linking the use of the judicial exceptions to particular fields of use (e.g., rheumatic disease therapy; MPEP 2106.05(e) and 2106.05(h)).
Therefore, the claims do not integrate the judicial exceptions into a practical application. See MPEP 2106.04(d) § I.
Because the claims recite an abstract idea and a natural phenomenon, and do not integrate those judicial exceptions into a practical application, the claims are directed to those judicial exceptions. Claims that are directed to judicial exceptions must be examined further to determine whether the additional elements besides the judicial exceptions render the claims significantly more than the judicial exceptions. Additional elements besides the judicial exceptions may constitute inventive concepts that are sufficient to render the claims significantly more (MPEP 2106.05).
Step 2B: Whether the Claims Contain Additional Elements that Amount to an Inventive Concept (MPEP 2106.05)
As noted above, several recited additional elements amount to insignificant extra-solution activity. Mere addition of insignificant extra-solution activity does not amount to an inventive concept that would render the claims significantly more than the recited judicial exceptions, particularly when the activities are well-understood or conventional (MPEP 2106.05(g)). The conventionality of recited additional elements that amount to insignificant extra-solution activity must be further considered.
The claims recite steps of assaying a biological sample using particular techniques, which serve to gather data necessary for performance of the claimed method. The specification states that “Methods of assaying may include any assay known in the art or described in the literature, for example, a microarray assay, a sequencing assay (e.g., DNA sequencing, RNA sequencing, or RNA-Seq), or a quantitative polymerase chain reaction (qPCR)” (pg. 113, para. 0455), and so indicates that assaying may generally be performed using conventional techniques.
The specification further indicates that the following recited assay technique may be performed with commercially-available products (see MPEP 2106.07(a) § III):
performing RNA-seq analysis (pg. 473, para. 1294: “mRNA isolation and sequencing were performed… using the miRNeasy Mini Kit (Qiagen, Germantown, MD, USA) per manufacturer's instructions… [and] on-column DNase digestion with RNase-Free DNase… RNA concentration was quantified using a NanoDrop 2000 system”).
Additionally, the courts have recognized performance of the following encompassed functions as well-understood, routine and conventional activity:
using polymerase chain reaction to amplify and detect DNA (Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377 (Fed. Cir. 2015);
electronically outputting a report detailing the comparison, i.e., computer-implemented processing and display of electronic data (EON Corp. IP Holdings LLC v. AT&T Mobility LLC, 785 F.3d 616, 622 (Fed. Cir. 2015)).
Hence, the encompassed activity is considered well-understood, routine and conventional. Well-understood, routine and conventional activity is insufficient to constitute an inventive concept that would render the claims significantly more than the judicial exceptions (MPEP 2106.05(d)).
Mere instructions to implement judicial exceptions using a generic computer are similarly insufficient to constitute an inventive concept that would render the claims significantly more than said judicial exceptions (see MPEP 2106.05(f)).
Mere instructions to apply a judicial exception in particular fields of use are similarly insufficient to constitute an inventive concept that would render the claims significantly more than said judicial exceptions (MPEP 2106.05(f) and 2106.05(h)).
When the claims are considered as a whole, they do not integrate the judicial exceptions into a practical application; they do not confine the use of the judicial exceptions to a particular technology; they do not solve a problem rooted in or arising from the use of a
particular technology; they do not improve a technology by allowing the technology to
perform a function that it previously was not capable of performing; and they do not
provide any limitations beyond generally linking the use of the judicial exceptions to particular technological environments and/or fields of use (e.g., rheumatic disease therapy; MPEP 2106.05(h)).
Therefore, the claims do not provide an inventive concept and/or significantly more than the judicial exceptions themselves. See MPEP 2106.05.
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole, are directed to judicial exceptions and lack an inventive concept. Hence, the claimed invention does not constitute significantly more than the judicial exceptions, so the claims are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Response to Arguments - Claim Rejections Under 35 USC § 103
In the Remarks filed 9/9/2025, Applicant traverses the rejections under 35 USC § 103. Applicant notes incorporation to independent claim 1 of limitations of now-canceled claim 12 (pg. 218, para. 5), and presents particular arguments regarding correspondence of the applied art and the limitations (including those incorporated from claim 1, by virtue of dependency) of now-canceled claim 12.
Applicant alleges that Liew is silent to the amended claim 1 feature of assaying an isolated biological sample to generate a data set by performing RNA-Seq analysis, instead disclosing generating data via microarray (pg. 219, para. 7 – pg. 220, para. 3).
The instant claims do not require generation of data via RNA-Seq, but rather allow for performance of RNA-Seq or quantitative polymerase chain reaction (qPCR). Liew discloses generating data via quantitative RT-PCR (para. 0188), which is considered to be a species of qPCR. Thus, the presented argument of deficiency in the disclosure of Liew is found unpersuasive.
Applicant alleges that Sasso and Quinn do not cure the deficiency of Liew regarding RNA-Seq, as Sasso discloses generating data via immunoassay while Quinn concerns identification of prognostic factors for undifferentiated arthritis in patients after drug treatment (pg. 220, paras. 4-5). As the alleged deficiency of Liew is not viewed as a fatal deficiency, given the alternative allowance of the claims for generating data via qPCR, neither Sasso nor Quinn are relied upon for teaching the feature of RNA-Seq. Thus, the argument is considered moot.
Applicant highlights the particular direction of Quinn to undifferentiated inflammatory arthritis (i.e., early inflammatory arthritis), and states that amended claim 1 is not directed to early inflammatory arthritis (pg. 220, para. 5).
While Quinn does particularly concern prognosis and treatment of early inflammatory arthritis, the removal of this particular species of arthritis from the claim text does not exclude Quinn as relevant prior art. The claims are expressly directed to identification and treatment of inflammatory arthritis, and early inflammatory arthritis is a species of inflammatory arthritis. See MPEP 2131.03 § I. Thus, the argument of distinct direction regarding the cited species of arthritis is found unpersuasive.
For the above reasons, the arguments are considered unpersuasive and the rejections have been maintained with respect to the pending claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 USC §§ 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 USC § 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 USC § 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 USC § 102(b)(2)(C) for any potential 35 USC § 102(a)(2) prior art against the later invention.
Claims 1, 4-5, 7-11, 13 and 17 are rejected under 35 USC § 103 as being unpatentable over Liew et al (US 2007/0269804; published 11/22/2007; on IDS filed 7/25/2024; previously cited) in view of Sasso (US 2018/0217141; published 8/2/2018; previously cited) and Quinn et al (Arthritis & Rheumatism 48(11): 3039-3045; published November 2003; previously cited). The new grounds of rejection presented herein were necessitated by Applicant’s amendment of the claims (filed 9/9/2025).
Claim 1 recites a method comprising: assaying a subject sample to generate gene expression data using RNA-seq or quantitative polymerase chain reaction (qPCR); using a computer to compare the generated data to reference expression data comprising gene signatures as recited, wherein a trained machine learning classifier is used to analyze or process the data to identify the state of the subject at an accuracy of at least 70%; and electronically outputting a report which identifies subject immunological state, disease state, disease susceptibility, predicted drug treatment response, and/or effectiveness of treatment. The claim further requires selection of the drug treatment, disease state, and/or sample type from recited alternatives.
Liew discusses “systems and methods for constructing classifiers that distinguish between trait subgroups using molecular marker data… [and] use of the classifiers in a wide variety of applications including: diagnosis; prognosis; prediction of disease; stage of disease or disease risk; monitoring disease progression and/or regression; monitoring disease reoccurrence and identifying risk of disease reoccurrence; determining and/or predicting response to treatment and/or treatment outcomes” (Abstract).
With respect to claim 1, Liew discloses measurement of RNA levels (i.e., gene expression data) in subject samples using known techniques (para. 0186), and exemplifies using quantitative RT-PCR, i.e., qPCR (para. 0188). Liew further exemplifies subject sample types including whole blood (para. 0322) and samples of specific blood cell types (i.e., purified cell samples; para. 0337) such as agranulocytes (i.e., peripheral blood mononuclear cells; para. 0335).
Liew further discloses identifying molecular markers that are differentially expressed in blood samples from patients with a disease as compared to blood samples from healthy patients (para. 0016), i.e., comparison to reference gene expression data comprising gene signatures. Liew discloses utilizing combinations of genes (para. 0277), and exemplifies at least the following genes:
EGR1, para. 0586 (found in modules ‘CD19 Skyblue’ and ‘CD33 Sienna3’ of Table 8);
G2AN, para. 0586 (found as GANAB in module ‘CD 19 Green yellow’ of Table 8);
HSPCA, para. 0586 (found as HSP90AA1 in modules ‘CD4 Turquoise’ and ‘CD19 Violet’ of Table 8, modules ‘IFNA2 Signature’, ‘IFNB1 Signature’, ‘IFNW1 Signature’, ‘Type I IFN Core Signature’ of Table 71A);
IL13RA1, para. 0586 (found in modules ‘CD4 Turquoise’ and ‘CD19 Brown’ of Table 8);
LAMC1, para. 0586 (found in modules ‘CD14 Pink’ and ‘CD19 Skyblue’ of Table 8);
PF4, para. 0586 (found in module ‘LDG-A’ of Table 8, module ‘LDG Module A’ of Table 43A, modules ‘Platelets-1’, ‘Platelets-2’ of Table 71B);
MAFB, para. 0586 (found in module ‘CD14 Yellow’ of Table 8);
TNFAIP6, para. 0586 (found in module ‘CD33 Sienna3’ of Table 8); and
TNF-alpha, para. 0460 (found as TNF in module ‘IFNB1 Alternative PW’ of Table 30, modules ‘INFK unique’, ‘Inflammatory Secrete’, ‘TNF Signature’, ‘IFNB1 ALTERNATIVE PW Increased transcripts’ of Table 71A, module ‘TH1’ of Table 71B, module ‘Inflammatory screen’ of Table 72B).
Liew thus exemplifies at least a plurality of gene signatures comprising transcripts of genes of one or more gene modules of Tables 1-2, 7-9, 13-16, 30, 32-34, 43A-43B, 49B, 71A-71B, 72B-72C and 74. Liew further discloses generation of a report indicating likelihood of the subject having any of different traits (para. 0314), and exemplifies traits including a disease state and responsiveness to drug therapy (para. 0478).
Liew additionally discloses training a neural network or SVM classifier on gene expression data to calculate trait likelihoods (paras. 0481-2 and 0526-7), i.e., a trained machine learning classifier is used to analyze or process the data set to identify the state. Liew discusses evaluating model effectiveness based on a number of exemplified performance scores, including percent correct predictions, i.e., accuracy (paras. 0285 and 0288). Liew additionally discloses ranking and eliminating models on the basis of score, e.g., eliminating classifiers with ROC scores, sensitivities, or specificities of less than 0.7 (paras. 0291 and 0296). Although Liew does not expressly describe eliminating classifiers with a percent correct prediction score of 0.7 (i.e., only retaining models with an accuracy of at least 70%), this is considered an obvious variant of the express teachings.
Liew exemplifies disease states including rheumatoid arthritis (a species of chronic condition, inflammatory condition, autoimmune condition, arthritis and inflammatory arthritis; para. 0319); drug treatments including nonsteroidal anti-inflammatory drugs and cortisone (a species of steroid and corticosteroid; para. 0194); and subject sample types including whole blood (para. 0322), and samples of specific blood cell types (i.e., purified cell samples; para. 0337) such as agranulocytes (i.e., peripheral blood mononuclear cells; para. 0335).
Liew also discloses administration of treatment (para. 0156), but does not disclose adjusting treatment as a function of gene expression data; or parenteral administration of treatment.
Sasso discusses methods for assessing response to inflammatory disease therapy (Abstract), and teaches assaying a subject sample to generate a quantitative score based on gene expression data (paras. 0008 and 0023). Sasso teaches that the score identifies subject disease state, and thereby allows for informed adjustment of therapeutic regimen to delay or prevent disease progression (para. 0060).
Sasso exemplifies assessment of rheumatoid arthritis (para. 0008), and teaches that most rheumatoid arthritis patients who do not receive optimal treatment early enough can suffer poorer outcomes and irreversible joint damage (para. 0061). Sasso does not teach parenteral administration of treatment.
Quinn discusses undifferentiated inflammatory arthritis, a diagnostic category comprising patients with potential for development of a persistent arthritis (e.g., rheumatoid arthritis) but not satisfying classification criteria for a persistent arthritis (pg. 3039, r. column). Quinn teaches that undifferentiated inflammatory arthritis is relatively common among rheumatology patients (pg. 3039, r. column), and may present opportunity for improved treatment outcomes as compared to persistent arthritis due to immunological differences (pg. 3040, l. column).
Quinn further teaches application of a three-stage treatment framework to patients with undifferentiated inflammatory arthritis, comprising 1) nonsteroidal anti-inflammatory drugs, 2) a first dose of a corticosteroid, and 3) a second dose of the corticosteroid in combination with disease-modifying antirheumatic drugs (DMARDS; pg. 3039, Abstract). Quinn further teaches administration of the corticosteroid, methylprednisolone, by intravenous or intraarticular injection (pg. 3041, l. column), i.e., parenteral administration.
Additionally, Quinn teaches that 72% of the studied patients received a single dose, while 30% received DMARDs (pg. 3041, r. column). Quinn further teaches that the second dose of methylprednisolone, combined with DMARDs, was only administered to patients whose inflammatory symptoms were not adequately treated by the first dose (pg. 3043, r. column). In this way, Quinn teaches that parenteral administration of certain drugs is an effective treatment option for arthritis patients.
With respect to claim 4-5 and 7-10, Liew exemplifies disease states including rheumatoid arthritis (a species of chronic condition, inflammatory condition, autoimmune condition, arthritis and inflammatory arthritis; para. 0319).
With respect to claim 11, Liew discloses treatment comprising administration of one or more compounds (para. 0156).
With respect to claim 13, Liew discloses analysis of blood samples taken from subjects who are undergoing treatment, with embodiments where evaluation of treatment is performed over days, weeks, months or years (paras. 0606-7). The plural term “years” indicates at least 2 years of treatment, thus Liew is considered to read on the limitations of the claim.
With respect to claim 15, Liew discloses diagnosis (i.e., identifying disease state) and predicting response to treatments for a subject, wherein treatments can be specific to a disease (para. 0132) and comprise administration of one or more compounds (para. 0156). In other words, identifying drugs for the treatment of a disease state.
With respect to claim 17, Sasso teaches reporting results as a visible display (para. 0118), i.e., a report. Sasso further teaches reporting 1) a disease activity score derived solely from biomarker data, and/or 2) a composite disease activity index that weighs biomarker data in combination with non-biomarker factors (para. 0119). In this way, Sasso teaches that a report may comprise different formats. Sasso teaches that the latter format may be utilized for further desired analyses in conjunction with non-biomarker data, while the former format includes this data natively (para. 0119).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented adjustment of treatment based on gene expression data, as taught by Sasso, within the classification method of Liew, because Sasso teaches that optimizing treatment is an enabled, highly important clinical application of gene expression data (paras. 0008 and 0061).
Said practitioner would have additionally implemented reporting of different formats because Sasso exemplifies reporting of different formats as providing different output utilities (para. 0119). Said practitioner would have had a reasonable expectation of success because Liew and Sasso both discuss analysis of gene expression data and treatment of rheumatic conditions.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have utilized the classification method of Liew to identify undifferentiated inflammatory arthritis, and implemented parenteral administration of treatment, because Quinn teaches that undifferentiated inflammatory arthritis is a widespread rheumatic condition (pg. 3039, r. column) which presents opportunity for improved treatment outcome once identified (pg. 3040, l. column).
Said practitioner would have additionally implemented parenteral administration of treatment because Quinn exemplifies an effective drug treatment option for rheumatic conditions, methylprednisolone, which is administered parenterally (pg. 3041, l. column; pg. 3043, l. column). Said practitioner would have had a reasonable expectation of success because Liew and Quinn both discuss treatment of rheumatic conditions.
In this way the disclosure of Liew, in view of Sasso and Quinn, makes obvious the limitations of claims 1, 4-5, 7-11, 13 and 17. Thus, the invention is prima facie obvious.
Response to Arguments - Double Patenting
In the Remarks filed 9/9/2025, Applicant requests that the Office hold the provisional rejections on grounds of nonstatutory double patenting in abeyance until the instant claims are deemed otherwise allowable.
“A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer… with a reply to the Office action… Such a response is required… [and] should not be held in abeyance. Only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated” (MPEP 804 § I.B.1).
Applicant has neither filed an appropriate terminal disclaimer nor filed showings that the claims subject to each rejection are patentably distinct from those of the reference patents and copending patent applications, in view of the cited art. Failure to treat the double patenting rejections is viewed as a minor deficiency, and Applicant’s response is nonetheless considered a substantial, bona fide attempt to advance the application. However, the double patenting rejections are maintained with respect to the pending claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Instant claims 1 and 8-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims of copending Application No. 16/679,109 (hereafter, “‘109a”), in view of Liew, Sasso and Quinn. ‘109a shares joint inventors (LIPSKY, Peter E.; CATALINA, Michelle D.; GRAMMER, Amrie C.; KEGERREIS, Brian; LABONTE, Adam; OWEN, Katherine A.; BACHALI, Prathyusha) and a common assignee (AMPEL BioSolutions, LLC) with the instant application. The new grounds of rejection presented herein were necessitated by Applicant’s amendment of the claims (filed 9/9/2025).
Instant clai