Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of the invention of Group I (claims directed to methods comprising determining gene expression levels) in the reply filed on 07/30/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicants’ additional species election of 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). Applicants assert that claims 1-3, 5-9, 14, 17-21 and 24-28 read on the election species; however, as noted in the requirement of 05/08/2025 independent claims 1 and 2 do not require the elected combination of genes (i.e.: they are directed to different subcombinations requiring less than the elected combination).
Claims 1-2, 5-8, 12, 15-23 and 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (e.g.: claims 1 and 2 and their dependent claims require non-elected subcombinations of genes) or to non-elected inventions (i.e.: arrays and computer-based methods), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/30/2025.
Claim Objections
Claim 3 is objected to because of the following informalities: the claim recites, in step c), the phrase “… each of another nine the genes BATF2 …”, where the phrase “… each of another nine [[the]] genes BATF2 …” is likely intended.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 3, 9, 14, and 24-28 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, 9, 14, and 24-28 are unclear over recitation of the limitation “determining in a sample of said individual an expression level of each of another nine the genes BATF2, GBP5, IFITM1, IL27, KCNJ2-AS1, SERPING1, STAT 1, TNFRSF21 and VAMP5”, as recited in step c) of claim 3, from which claims 9, 14, and 24-28 depend. The recitation is unclear over the use of the phrase “another nine” because in the listing of nine genes in step c), the level of two of the genes (i.e.: BATF2 and IFITM1) were already determined in step b). So it is unclear how these genes are considered “another nine” genes. The phrase may be made more clear in this regard if amended to recite “determining in a sample of said individual an expression level of each of [[another]] the nine [[the]] genes BATF2, GBP5, IFITM1, IL27, KCNJ2-AS1, SERPING1, STAT 1, TNFRSF21 and VAMP5”.
Claims 3, 9, 14, and 24-28 are unclear the steps recited as e1) and e2) at the end of claim 3, from which claims 9, 14, and 24-28 depend. The claims are unclear because the lack of any conjunction between step e1) and e2) makes it unclear if the claimed methods requires both of the steps to be performed (i.e.: e1) and e2)), or if the limitations of the claims are met if either step is performed (i.e.: e1) or e2)).
Claim 14 is unclear over recitation of the phrase “said determining step is performed in vitro”, because the claim depends form claim 3 which recites several steps of “determining” (e.g.: part i) of the preamble; step a), step b), step c), step e1) and step e2). Thus, it is unclear what particular determining is addressed with the singular “said determining step” as recited in claim 14.
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 3, 9, 14, and 24-28 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 there are no practical steps dependent upon the outcome or results of the calculating and determining. The claims end with the mental conclusion of determining the end of therapy or the status of tuberculosis infection.
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.
Claim Rejections - 35 USC § 112 – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3, 9, 14, and 24-28 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 encompass the analysis of tuberculosis infection in any subject organism, whereas the specification provides only an example of determinations made for human subjects (e.g.: the “patients” as set forth on page 17 of the specification) without any indication of how the calculations of the instant specification would be adjusted to be used in other subject organisms. In this regard it is relevant to point out that Hoshikawa et al (2003) teaches unpredictability with regard to applying gene expression results among different organisms.
The claims generically encompass the analysis of any type of sample, and specifically recite sputum as a sample type (i.e.: claim 24), whereas the specification provides only an example of determinations made using blood samples (e.g.: “whole blood samples” 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 other sample types. In this regard it is relevant to point out that Cobb et al (2002) teaches that different levels of gene expression may be identified in different tissue types even when the same pathological condition is present.
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 claim 3) 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 claim 3) determination of expression levels of BATF2, GBPS, IFITM1, IL27, KCNJ2-AS1, SERPING1, STAT1, TNFRSF21 and
VAMPS, 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.
Conclusion
No claim is allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571)272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683