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 .
This action is in response to papers filed 9/29/2025.
Applicant's election with traverse of Group I and the genes of BTN3A3, ACSL5, ECHDC2, VAMP4, NDFIP1, ATP2B1, SLC25A3, KNOP1, TMEM67, and CSKMT in the reply filed on 2/28/2025 is acknowledged.
Claims 1, 3-14 are pending. Claims 2 and 15 has been cancelled.
Claims 12-14 are withdrawn as being drawn to a nonelected invention.
The following rejections for claims 1 and 3-11 are maintained or newly applied necessitated by amendment. Response to arguments following.
This action is FINAL.
Withdrawn Objections and Rejections
The Claim objections made in the previous office action is withdrawn based upon amendments to the claims.
The 35 USC 112(b). 35 USC 102 and 35 USC 103 rejections made in the previous office action are withdrawn based upon amendments to the claims.
Maintained Rejection Improper Markush Grouping
Claims 3-5 are rejected under the judicially approved ''improper Markush grouping'' doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch, 631 F.2d 716, 719-20 (CCPA 1980). A Markush claim contains an ''improper Markush grouping'' if: (1) the species of the Markush group do not share a ''single structural similarity,'' or (2) the species do not share a common use. 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. However, when the Markush group occurs in a claim reciting a process or a combination (not a single compound), it is sufficient if the members of the group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. See MPEP § 803.02.
Here each species is considered to be a method for predicting prognosis from a Bcell lymphoma wherein the genes are selected from claims 3-5. As such each gene or combination is considered a distinct species.
The recited alternative species in the groups set forth here do not share a single structural similarity, as each method relies on detection of different gene and gene combinations). Each gene is itself located in a separate region of the genome and has its own structure. The gene recited in the instant claims do not share a single structural similarity since each consists of a different nucleotides that occurs at a different location on human genome. For example, SLAMF6 and ACSL5 have unique sequences and comprise different nucleotide alterations at different locations on the genome.
The only structural similarity present is that all detected positions are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with risk for development of lethal complications of sepsis. The association between the claimed markers is not considered as 'property' as the association is a statistical construct, it is a conclusion based on analysis of a specific population and may not be present in subject outside of the population assayed. Further there is no evidence the association has been replicated (or was known in the art). While the instant specification asserts markers have a common function of being correlated with the asserted phenotype, the association between the claimed genes is not clear from their very nature. If the instantly claimed SEQ ID Numbers are placed in a group with an equal number of other gene fragments the skilled artisan could not differentiate those associated with a phenotype from those that are not associated with a phenotype. Thus the one of skill in the art could not identify those genes or gene combination that are asserted to be associated with the phenotype by their very nature. Thus the instant claims have not met the requirements of a proper Markush group.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Response to Arguments
The reply traverses the rejection. A summary of the arguments provided below with response to arguments following. The reply asserts that that the claims have particular genes with over or under expressions and as such provide a particular use (p. 8). These arguments have been reviewed but have not been found persuasive.
The MPEP directs that it must be clear from their very nature or from the prior art that all of them possess this property. The reply asserts that the genes are all similar based upon the particular expression levels. However, this is not clear from the very nature or provided in the prior art. There is no evidence in the record to make clear that from their very nature that these different genes have some particular expression associated with a particular function. As such the Markush rejection has been maintained.
Maintained Claim Rejections - 35 USC § 112
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 1 and 3-11 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.
The claims are drawn to predicting the prognosis of a subject suffering from a B-cell lymphoma comprising the step of detecting the status of DNA binding activation of the RelB protein. The claims further are draw to measuring the expression level of BTN3A3, ACSL5, ECHDC2, VAMP4, NDFIP1, ATP2B1, SLC25A3, KNOP1, TMEM67, CSKMT to detect status.
Therefore the claims are drawn to any sample, subject, expression level values and determining any prognosis of any subject. As provided below, the specification has not described the breath of the claims in view of the functionality.
The specification provides samples from tumor from human patients with B-cell lymphoma (para 92). However, the specification has not provided guidance that the expression and activation would be similar across samples/species. As provided below, the art teaches that expression analysis with a phenotype is not directly correlative between sample types and subjects.
The specification asserts that RelB activation is correlated with worse overall survival (para 107).
The specification provides that not all genes transcriptional signatures associated with RelB are linked to RelB activation (para 110). Table 2 provides particular expression of specific genes linked to RelB activation (starting on p. 19). Therefore although the specification provides specific examples of increased and decreased expression of specific genes, the specification has not provided support of the breadth of the language which would include any level of expression of any gene associated with RelB.
The art does not provide the critical structural elements for the asserted functionality. In particular Enard et al. (Science 2002 Vol 296 p. 340) teaches that even between closely related species gene expression patterns differ (abstract). Enard et al. teaches that mRNA expression levels are different between humans, chimpanzees, orangutans and rhesus marcques (p. 340 1st column last sentence-2nd column 1st paragraph). Enard et al. teaches that there are a large number of quantitative differences in gene expression in closely related mammals (p. 342 2nd column last paragraph). Therefore the art teaches that even between very closely related mammals there is a divergence of gene expression. As such Enard et al. teaches that merely being a biomarker in one species would not be sufficient to provide support for the structure in other species.
The art of Cobb et al (Crit Care Med 2002 Vol. 30 p. 2711) teaches the unpredictability in analysis of gene expression in spleen and liver sample from septic mice. Notably, the reference teaches that, when compared to a non-septic sample, the relevant expression profiles of the septic mouse spleen and the septic mouse liver contain different nucleic acids at different levels (Table 1; p.2714, middle col., lns.2-8). As such the art teaches that expression levels of the same nucleic acids in different tissue samples differ. Therefore the art indicates that an association of signal separation of expression level to subtyping in one sample would not be functionally correlative to an association to any other sample type.
Accordingly, the specification has not provided the critical elements needed in the structure to predictive functionally. Therefore the specification lacks written description of any subject representative of the broadly claimed genus.
In analysis of the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note regarding genus/species situations that “Satisfactory disclosure of a ``representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.” (See: 'Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.)
Response to Arguments
The reply traverses the rejection. A summary of the arguments provided below with response to arguments following. The reply asserts that the claims have been amended to clarify the steps an to define creating an expression signature using a plurality of the RelB activation dependent genes (p. 9). The reply asserts that the claims clarify over and under expression relative to a healthy subject (p. 9).
These arguments have been reviewed but have not been found persuasive.
Although the claims have been amended to “RelB activation dependent genes, wherein the activation is detected by measuring an expression level of the plurality of RelB activation dependent genes from an expression signature in the biological sample”, the specification has not provided the critical structure to determine which genes would be activated. It appears based upon the claim language that determine which genes are RELB activated dependent, these have to first be determined by determining expression signatures of the genes. However, the specification does not provide the critical structures needed to have this expression signature and as such the person skill in the art would not be readily able to determine which genes would be encompassed in this genus versus which genes would not be encompassed. Furthermore, the claims are drawn to any subject type and sample type and as provided above such expression correlations in different samples are not functionally equivalent. The claims are drawn to using expression to determine select a treatment regimen to maximize survival” however, the specification has not provided which of the genus of relB activation dependent genes would functionally determine any type of treatment and the response of maximum survival.
Newly Applied 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 and 3-11 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 1 and 3-11 are indefinite over step b of claim 1. The claims appear to compare the signature of a to a “control sample of health tissue”. This phrase is not clears it is not clear if the claims are intending to encompass tissue samples from a patient without B cell lymphoma or if the claims are intending to encompass tissue samples that are not in areas where lymphoma occurs”. Furthermore the claims appear to compare any “biological sample” in a to a tissue and as such it is not clear if there requires further method steps for such a comparison.
Claims 1 and 3-11 are indefinite over step c of claim 1. Step c requires a difference, however, step b only requires a comparison and does not require a step to determine differences between the two.
Modified 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, 3-11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception (natural phenomenon) without significantly more. The claim(s) recite(s) a method of prognosis of Bcell lymphoma based upon detection of the status of DNA binding activation of RElB protein. This judicial exception is not integrated into a practical application because the steps does not integrate the judicial exception of correlation to prognosis and detection of the status. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps of providing and assaying encompass well known and routine methods of hybridization.
Question 1
The claimed invention is directed to a method that recites judicial exception. The correlation of the prognosis of Bcell lymphoma
Question 2A – Prong 1
Claim 1 recites the patent ineligible concepts of natural phenomenon. The correlation of prognosis of Bcell lymphoma and the determination of naturally occurring activation is considered a natural phenomenon. As in Mayo Collaborative Services v. Prometheus, the recited relationship to the disease or condition is a natural phenomenon that exists apart from any human action.
Question 2A – Prong 2
The judicial exceptions are not integrated into practical application because the claims do not recite any additional elements that integrate the judicial exceptions into practical application of the exceptions.
The claims provide additional steps of detecting activation status and dependent claims to wherein activation is determined by measuring expression levels. However, this steps are considered well known based upon the knowledge of expression assays in the prior art (as discussed below).
Accordingly, the claims are directed towards judicial exception.
Question 2B
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions because the claims do not add a specific limitation other than what is well-understood, routine and conventional in the field. The step of providing a sample and assaying to determine expression levels employs only potential techniques that were known to one skilled in the art. Jardin et al (US Patent Application Publication 2017/0016074 Jan 19, 2017) teaches detection of expression of the recited genes which are taught by the instant specificaoin to be on the HGU133 Affymetrix gene chip (para 137, 226, 246 and Table 2). The instant specification teaches that HGU133 Affymetrix gene chip was used to screen genes associated with RelB in Bcell lymphoma patients (para 92). The instant specification teaches routine methods of detecting expression including RT-qPCR and nanostring (p. 33).
The claims as a whole do not amount to significantly more than the judicial exceptions themselves. The steps outlined above are merely well-understood, routine and conventional activities previously known in the industry, specified at a high level of generality, applied to the steps of assigning and comparing. The claims do not recite additional elements that amount to significantly more than the judicial exceptions.
For those reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments
The reply traverses the rejection. A summary of the arguments provided below with response to arguments following. The reply asserts that the claims add particular steps including defining the concept of preparing an expression signature in order to prognosis or provide a choice of a treatment (p. 9). The reply asserts the creation of any expression signature for the particular patient which would require steps of human intervention and innovation (p. 9).
These arguments have been reviewed but have not been found persuasive.
It is noted that the correlation of expression data to treatment regimen selection or prognosis would be considered a judicial exception as this correlation exists in nature. Furthermore it is noted that detection signatures of expression in step is considered a routine step that is performed with any expression assays on naturally occurring genes. The step of b is considered an abstract steps as the comparison can be performed using the mind by looking at data printouts. The step of c as noted above appear to be the judicial exception. There does not appear to be any integration of the judicial exceptions to a step that is not routine and well-understood. Therefore the rejection has been maintained.
Conclusion
No claims are allowed. 14. 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 KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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, Wu Cheng (Winston) Shen can be reached on 5712723157. 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.
/KATHERINE D SALMON/Primary Examiner, Art Unit 1682