Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office Action is in reply to Applicants’ correspondence of 04/21/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 07/30/2025 Applicants elected the invention of Group I (claims directed to methods comprising determining gene expression levels); the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicants additionally elected the species that is the combination of genes that is CD274, FAM20A, GYG1, HISTH1B, LPCAT2, TRIM27, RPAP3, A_33_P3281041, BATF2, C2, GK3P, IFIT2, IFITM1, KREMEN1, PDE4D, BATF2, GBP5, IFITM1, IL27, KCNJ2-AS1, SERPING1, STAT1, TNFRSF21, and VAMP5 (i.e.: a combination of 22 genes, noting that the genes BATF2 and IFITM1 are repeated in the list).
Withdrawn Claim Objections
The objection to claim 3, as set forth on page 3 of the Office Action of 10/23/2025, is withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejections of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 3-4 of the Office Action of 10/23/2025, are withdrawn in light of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 3, 14, and 25-28 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.
Claims 3, 14, and 25-28 are unclear over recitation of the limitation “whereby the calculation is conducted as shown in table 4”, as recited in claim 3. MPEP 2173.05(s) provides guidance with regard to the reference to figures and tables in claims:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience."
Maintained Claim Rejections - 35 USC § 101
Modified/Newly Applied as Necessitated by Claim Amendments
Claims 3, 14, 25-28 and 31-36 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (natural phenomena, abstract ideas/mathematical concepts) without significantly more.
The claim(s) recite(s) methods of determining a need for therapy and making a diagnosis of tuberculosis where the determinations and diagnoses are based on measured gene expression levels. The claims are thus directed to abstract ideas that are a mental process of evaluating data and information to reach a conclusion (e.g.: see MPEP 2106.04(a)(2)(III)). Additionally, the claims includes steps of calculating a score (e.g.: step a) of claim 3) and a value (e.g.: step b) of claim 3) using determined gene expression levels, which mathematical calculations (e.g.: see MPEP 2106.04(a)(2)(I)(C)). Furthermore, where the claims are directed to the asserted association between gene expression levels and tuberculosis infection status, or treatment response, such an association is a natural phenomenon (e.g.: see MPEP 2106.04(b)(I))
The judicial exceptions of the claims are not integrated into a practical application because the claims encompass methods in which no practical steps are performed that are dependent upon the outcome or results of the calculating and determining.
The claims encompass methods where a therapy is discontinued, which means that any therapy is stopped or halted. Where a therapy is stopped, there is no additional practical step required in the method.
Additionally, the claims only broadly recite “a drug therapy regimen”. Where the claims do not require any particular drug treatments, and do not set forth any functional treatment of the recited regimen (e.g.: the claims do not require a drug therapy regimen for the treatment of tuberculosis), such a recitation is not sufficient to create a method that is significantly more than the included judicial exception(s). MPEP 2106.04(d)(2)(a) provides guidance in this regard, providing:
… consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the practical steps of the claims are the typical data gathering steps related to gene expression in a subject with tuberculosis infection. The steps, recited at a high level of generality (e.g.: determining in a sample of saif individual an expression level of each of six genes) are well understood, routine and conventional in the related art. See for example the insntat specification at page 19 which teaches that the analysis of RNA expression was performed using the commercially available human 4 x 44K V2 gene expression array from Agilent. And Guerra-Laso et al (2015) which teaches microarray analysis of RNA obtained from tuberculosis infected cells using Whole Human Genome Microarray 4 x 44K v2, an Agilent array for the detection of containing 41,000+ unique human genes and transcripts.
Based on the considerations as detailed above, the claims are directed to a judicial exception without significantly more.
Response to Remarks
Applicants have traversed the rejection of claims made under 35 USC 101 as maintained above. Applicants have argued (p.8 of the Remarks of 04/21/2026) that “the individual be treated by an individualization of the drug therapy regimen of said individual whereby the regimen is discontinued when the therapy-end is reached.” The argument is not persuasive because, as set forth in the rejection, discontinuing a treatment, as encompassed by the claims, does not require any additional practical steps such that the judicial exception(s) of the claims can be considered to be integrated into a practical application. Additionally, as set forth in the rejection, the broadly recited “drug therapy regimen” is not a requirement for any particular treatment.
Maintained Claim Rejections - 35 USC § 112 – Written Description
Modified/Newly Applied as Necessitated by Claim Amendments
Claims 3, 14, 25-28 and 31-36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Arad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number’ of species. The "structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875.
The rejection of claims for failing to have an adequate written description in the application as originally filed is relevant to several aspects of the claimed methods. The claims are drawn to methods related to the determination of the end of tuberculosis therapy in a subject, and diagnosis of tuberculosis in a subject, an encompass considerable breadth over various elements of the claims.
The claims generically encompass the analysis of any gene expression analyte (e.g.: mRNA or protein), whereas the specification provides only an example of determinations made using RNA samples (e.g.: “total RNA” as set forth on page 19 of the specification) without any indication of how the calculations of the instant specification would be adjusted to be used with a different analyte. In this regard it is relevant to point out that Chen (2002) teaches that it is common for protein expression to be discordant with mRNA expression levels even in matched samples (e.g.: Figure 3)
The steps of the claims include calculating values and scores (steps a) and b) of each of claims 3 and 31) using determined gene expression values, but do not set forth any manner in which these values or score are calculated, thus generically encompassing any score or values that are made with any combinations of any weighted gene expression measurements. Such breadth in the methods, in combination with the functional requirements of the claims with regard to treatment requirements and infection status, is relevant considering the recognized natural variation in gene expression among different individuals, as taught by Cheung et al (2003). With regard to the score that is required to be calculated in step a) of claim 3, the specification teaches (e.g.: page 22) only a particular formula for the calculation of a disease severity score (DSS):
Score= -62.19940 + CD274*0.70954 + FAM20A*0.09335 + GYG1*1.68156 + HIST1H1B*3.71256 + LPCAT*1.18746 + TRIM27*0.14288
that is useful in the methods as claimed. And with regard to the value that is required to be calculated in step b) of claim 3, the specification teaches (e.g.: page 23) only a particular formula for the calculation of remaining days of therapy:
Days till therapy end= (-3170.49 + RPAP3*113.27 + A_33_P3281041 *275.53 + BATF2*86.86 + C2*-57.62 + GK3P*-102.19 + IFIT2*-101.94 + IFITM1*73.64 + KREMEN1* 75.52 + PDE4D*76.23 +MDR*235.74)-Days since therapy start
that is useful in the methods as claimed. It is further noted that the calculation of remaining days of therapy, as provided by the specification, requires inclusion of a value indicative of the presence or absence of multidrug- and extensively drug-resistant tuberculosis (i.e.: +MDR*235.74; where in case of MDR-TB the numerical value is 1, while in the absence of MDR-TB, the numerical value is 0).
The claims further require (step c) of each of claim 3 and 31) determination of expression levels of BATF2, GBPS, IFITM1, IL27, KCNJ2-AS1, SERPING1, STAT1, TNFRSF21 and
VAMP5, and the use of these levels in combination with the score and value of steps a) and b) to make the determinations of treatment requirements and infection status. But the specification does not provide any methodological steps in which the levels of step c), or the combination of a score and a value and the levels, obtained from a sample from a subject, are evaluated to determine treatment requirements and infection status of that individual subject. The specification only provides (p.10) that the method takes into consideration the expression level of additional genes, namely, the expression level of the genes BATF2, GBPS, IFITM1, IL27, KCNJ2-AS1, SERPING1, STAT1, TNFRSF21 and VAMPS. There is no disclosure in the specification as to how the determination of these levels in an individual sample, as set forth in the claims a priori provides a measure of treatment requirements and infection status. In this regard it is noted that the specification provides (p.23) only that scores, values, and expression levels can be combined as part of a random forest analysis using a population of patients to determine an association between the scores, values, and expression levels and when a patient reaches the end of therapy. The example of the specification does not provide information that can be used to determine treatment requirements (e.g.: when therapy will end) with the analysis of a sample form a single subject. Further in this regard it is noted that while the specification teaches that any sort of machine learning analysis will determine the required associations (e.g.: p.16-17), the specification only provides an example using random forest (RF) classifications with 5,000-fold iterations. This is relevant where the related art, such as Uddin et al (2019) teaches that different algorithms for classification may provide different results.
Thus, given the broadly encompassed methods, in combination with the functional requirements of the analyses, and teachings of the related art, it is the conclusion that the methods as claimed are not adequately described by the application as originally filed.
Response to Remarks
Applicants have traversed the rejection of claims made under 35 USC 112(a) as maintained above. Applicants have argued (p.8-9 of the Remarks of 04/21/2026) that the claims are amended to recite analysis of blood samples in human subjects The argument is not persuasive because, as set forth in the rejection, the claims boradly encompass the analysis of any analyte (e.g.: protein levels) without any teachings in the specification regarding the use of such levels (i.e.: the specification taches only RNA analysis) in calculating tuberculosis treatment related values and scores. Additionally, as set forth in the rejection, the application as filed does not provide an adequate description of how the expression levels of BATF2, GBP5, IFITM1,IL27, KCNJ2-AS1, SERPING1, STAT1, TNFRSF21 and VAMP5 are combined with each other and with calculated severity scores and days-till-therapy-end values to arrive at a probability that therapy-end has been reached.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/ Primary Examiner, Art Unit 1683
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