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 .
Based upon the arguments made in the reply of 7/22/2025 the groups have been rejoined. The species election of MAP4K1, TBX3, and CCL21 has been maintained. The response traverses the species as it would not impose an undue search burden (p. 3). This arguments has been reviewed but is not found persuasive as each species of gene would require a different specific search in the electronic databases.
The requirement is still deemed proper and is therefore made FINAL.
This action is in response to papers filed 1/28/2026.
Claims 1-4, 7, 9, 11-15, 18, 20, 22, 23, 25, 27, 32, and 41-42 are pending. Claims 5-6, 8, 10, 16-17, 19, 21, 24, 26, 28-31, and 33-40 are cancelled.
The following rejections are maintained with response to arguments following.
This action is FINAL.
Withdrawn Rejections
The 35 USC 112b, 35 USC 102 rejection made in the previous office action is withdrawn based upon amendments to the claims.
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 1-4, 7, 9, 11-15, 18, 20, 22, 23, 25, 27, 32, and 41-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for measuring metrics, does not reasonably provide enablement for correlation of metrics and treatment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
Nature of the Invention/Breadth of the Claims
The instant claims are drawn to a of correlation of determining metric immune infiltration, metric poor tumor differentiation , mutation tumor state and combinations thereof.
Teaching in the specification
The specification asserts that TMB and high levels of tumor infiltrating T cells have been associated with immunotherapy but integrative models have not (p. 13).
The instant specification does not provide guidance for the correlation of the breadth of these terms with CPB immunotherapy. The reply asserts that T cell burden (TCB) and B cell burden (BCB) was measured based on rearranged TCF/Ig DNA such that patients with melanoma with high TMB together with either high TCB or high BCB survived longer (p. 13). The specification asserts that MAP4K1 combined with TBX3 overexpression provides predictions of outcome after checkpoint blockade in melanoma (p 13-14). The specification states that patients with high immune infiltrate and low expression of TBX3 prior to checkpoint blockade had longer survival in melanoma (p. 14).
Although the specification describes some correlations, the specification does not provide guidance to the predictable correlation of any measurement of metric immune infiltration and metric of poor tumor differentiation or tumor state. Further, the specification asserts that metric of immune infiltration is a measure of T cell burden or B cell burden by measuring the number of somatic mutations or copy number alterations (para 8), however, the claims are limited to measure of MAP4K1 expression. The specification has not provided that expression of MAP4K1 is equivalent to a measure of T cell burden or B cell burden by measuring the number of somatic mutations or copy number alterations. Furthermore even when the claims are interpreted as a measure of T cell burden or B cell burden by measuring the number of somatic mutations or copy number alterations the specification has not provided guidance to which of these number of somatic mutations or copy number alternations would provide for administration of any CPB immunotherapy or administrations of standard of care therapy.
The claims further require a measure of “a metric of poor tumor differentiation or tumor state”. The specification states that poor tumor differentiation can be a measure of TBX3 or AGER (para 6). However, the specification only provides correlations of particular cancer and particular treatments to expression levels of these genes. The specification further states that poor tumor differentiation is a measure of a second metagene associated with an OS of less than one year (para 7). The specification provides some genes that are asserted to be encompass with this second metagene (para 7), however, it is not clear the breadth of the second metagene as it is associated with OS of less than one year in any species or any cancer. The specification has not provided which of the metagenes would be correlative in any species or any cancer. Furhtermore, the second metagene would encompass genes that have not been determined to have an OS of less than one year, and as such it is not clear which genes would be encompassed as it would be based upon measurement and correlations that have not been described by the specification.
State of the Prior Art/Level of Predictability in the Art
The skilled artisan cannot envision the steps, specific assay methods and specific measurement thresholds that are required to establish specific correlations of immunotherapy agents. Although the prior art teaches expression of genes that would be encompassed by metric of immune infiltration and poor tumor differentiation or mutation tumor state, the prior art does not describe the critical components to associated these measurements with treatment determinations and administration.
In general, the art regarding establishing expression levels within different species is unpredictable. Enard teaches that even between closely related species gene patterns differ (Enard et al. Science (2002) Vol. 296, p. 340, Abstract). Enard teaches that mRNA expression levels are different between humans, chimpanzees, orangutans and rhesus marcques (Enard, p. 340 para spanning 1st col-2nd col). Enard teaches that there are a large number of quantitative differences in gene expression in closely related mammals (Enard, p. 342 2nd col, last para).
Conclusion
Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Response to arguments
The reply traverses the rejection. A summary of the arguments is provided below with response to arguments following. The reply asserts that the instant claims are directed towards methods of treatment and methods of detecting tumors responsive to a CPB therapy (p. 12). The reply asserts that the recited metrics are used to inform the treatment or to detect responsive tumors (p. 12). The reply asserts that the instant specification discloses that high levels of immune cell infiltration as quantified by measures of rearranged TCR sequences or rearranged Ig in RNA seq were associated with survival and response (p 13). The reply asserts that the scope of the recited metric of immune cell infiltration is demonstrated in the examples and positive associated with subject survival and response to CPB immunotherapy (p. 13). The reply asserts that genes such as TBX3 and AGER are overexpressed in patients with overall survival rates less than a year and therefore associated with poor outcomes (p. 13). The reply asserts that application therefore encompass methods of treated a selected subject (p. 13). The reply asserts that a correlation between immune infiltration and poor tumor differentiation or tumor state is not recited in the claims (p. 13). The reply asserts that by pairing two metrics that inventions were able to outperformed model predictions of response and survival, however, this is not a correlation between the metrics (p 14). The reply asserts with regard to claims 4 and 15 the each of these genes is provided to be one of the first or second metagenes and therefore there is no ambiguity (p 14). The reply asserts that the action overlooks the working examples with many markers and survival and or CPB immunotherapy (p. 14). The reply asserts that the that the instant inventors made the key discovery of a relationship between metrics of immune infiltration and/or merits of poor tumor differential or tumor state and response to treatment (p. 14).
These arguments have been reviewed but have not been found persuasive.
The reply asserts that there is no claimed correlation, however, the administration of CPB immunotherapy is only provided to subjects that have been selected based upon metric of immune infiltration and a metric of poor tumor differentiation or tumor state. As such the claims requires a determination of associations of theses to the selection of the subject that is treated. The specification asserts that metric of immune infiltration is a measure of T cell burden or B cell burden by measuring the number of somatic mutations or copy number alterations (para 8), however, the claims are limited to measure of MAP4K1 expression. The specification has not provided that expression of MAP4K1 is equivalent to a measure of T cell burden or B cell burden by measuring the number of somatic mutations or copy number alterations. Furthermore even when the claims are interpreted as a measure of T cell burden or B cell burden by measuring the number of somatic mutations or copy number alterations the specification has not provided guidance to which of these number of somatic mutations or copy number alternations would provide for administration of any CPB immunotherapy or administrations of standard of care therapy. With regard to the particular genes measured, the specification only provides particular cancer and particular treatments to expression levels of these genes, furthermore it is not clear that these genes would be used for selection of treatment of any patient (including any species). Therefore as discussed above, the specification does not provide enablement for predictable selection of a patient.
Claim Rejections - 35 USC § 112
Claims 4, 11, 15, and 23 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of metagenes is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The genes are distinct structure that have different nucleic acid structures. Further, the is no common use based upon the very nature of the metagenes. Rather, the metagene determination must have been determined based upon score analysis performed by the instant specification. There is no identical that this functionality would have been known based upon their very nature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to arguments
The reply traverses the rejection. A summary of the arguments is provided below with response to arguments following. The reply asserts that the metagenes are grouped based upon the inventors discovery that these metagenes were associated with positive treatment outcomes and the second metagenes are associated with negative treatment outcomes (p. 16). The reply asserts that therefore these groupings were demonstrated to be interchangeable (p. 16). These arguetmsn have been fully reviewed but have not been found fully persuasive.
The meta genes as provide do not share a structural similarity as the genes recited only share a structure of being a nucleic acid. However, this structure is not considered part of the Markush group as all genes have such a structure. Further the reply argues that the memembers must share a common use but that use does not have to be “of the very nature” for biological Markush groups. The reply asserts that the Markush genes recited can be used interchangeably. MPEP 2117 IIA states “Thus, a Markush grouping is ordinarily proper if all the members of the group belong to a recognized class (whether physical, chemical, or art recognized) and are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed invention, and it is clear from their very nature or from the prior art that all members possess this property”. Herein as noted in the reply the property is not part of the “very nature or from the prior art” but rather the property is based upon the inventions screening and measurement of genes to determine correlations.
Conclusion
No claims 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 KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/Primary Examiner, Art Unit 1682