FINAL ACTION
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 responsive to the Amendment filed 07 January 2026. Claims 30 and 36 have been amended, claim 35 has been canceled, and claim 37 has been added. All prior rejections of claim 35 are moot in view of the cancelation of that claim. Claims 16-29 and 31-34 remain withdrawn, and claims 30 and 36-37 are under consideration herein. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive for the reasons that follow. Claims 30 and 36-37 remain/are rejected for the reasons given below, which include new grounds of rejection necessitated by Applicant’s amendments. Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
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
Applicant’s election of a PD-1/PD-L1 immune checkpoint inhibitor, and the set of genes comprising PD-L2, CTLA-4, LAG3, TLR4, and FOXP3, in the reply filed on August 18, 2025 is again 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)).
Claims 16-29 and 31-34 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 18, 2025.
Claims 30, 36, and 37 recite the elected species (see text of independent claim 30) and are under consideration herein. The prior art continues to apply against the claims as directed to the elected species (see rejection(s) below).
Comment Regarding Amendments to the Specification
It is noted that Applicant’s amendments to the specification filed 07 January 2026 have been reviewed and entered. The amendments overcome an objection set forth in the prior Office action, and correct other minor informalities.
Claim Interpretation
With regard to claims 30, 36, and 37, while it is noted that the use of the term “subject” rather than “patient” in the preamble of the claim does not render the claim indefinite given the location of the terminology (and the fact that “patient” is used consistently throughout the body of the claim), it is suggested that the claim be amended to employ consistent terminology throughout.
Claim Rejections - 35 USC § 112(b)/second paragraph
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.
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 30, 36, and 37 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 30, 36, and 37 are indefinite over the recitation in amended independent claim 30 of the limitation “the likelihood…is inversely correlated with the fold change of the expression for the set of genes”, because it is not clear what is encompassed by such a “likelihood”, particularly as it is unclear what “fold change” is being referenced, and which “set of genes” (it is noted that this rejection is analogous to a rejection of slightly different language in the prior Office action, as the language “susceptibility for having a” has been replaced with “likelihood of”). The claim previously references determination of expression levels of a “set of genes” in two different types of samples, a “tumor sample” and a “normal histologically matched sample”. There is no reference to any type of comparison necessarily resulting in a “fold change”, and the reference to “the fold change of the expression for the set of genes” could potentially refer to expression levels in the tumor sample or the matched normal sample. Further, if the reference to a ”fold change” is intended to reference, e.g., relative expression level values of the two types of samples, the claim should be reworded to state this (and to make clear what any “change” is relative to, i.e., does this refer to tumor sample levels relative to normal sample levels, or the opposite of this). Given this lack of clarity, it is also generally unclear how likelihood is to actually be determined via the practice of the method. The Reply of 07 January 2026 traverses the prior rejection on the grounds that “the claim clearly recites the set of genes…within the body of the claim”, and that the “amendments to the claims have rendered” the other issues raised moot. In response, it is noted that the claims involve both a “set of genes” in a tumor sample and a “set of genes” in a “histologically normal sample”, and further that the present claim language still does not make clear what type of “fold change” is being referenced/required by the claims. The claims as written continue to potentially encompass various types of fold changes – e.g., tumor vs. control and/or control vs. tumor (preferred types discussed in the specification, but with the present claim language not clearly limited thereto), as well as, e.g., changes at one time point as compared to another); thus, the boundaries of the claims as presently amended remain unclear.
Claims 30, 36, and 37 are also indefinite because it is unclear whether the claims do or do not require performance of the “selecting” and “administering” added to the end of claim 30, and also unclear what would be sufficient to meet the requirement of “selecting….based on a fold change higher than 1.3”. First, the language “selecting a patient….based on a fold change higher than 1.3” is unclear because: a) the nature of what is meant and encompassed by “fold change” in the context of the claimed invention is unclear (as discussed above); and b) the meaning and boundaries of the language “based on a fold change” are unclear, particularly with regard to what activities would and would not be sufficient to be considered as selecting “based on a fold change”. Second, independent claim 30 may reasonably be interpreted as either requiring or not requiring the recited “selecting” and “administering”, which renders the boundaries of the claims unclear. Some persons of skill in the art would interpreting the language “selecting a patient….based on…” followed by “administering….to the selected patient” as a requirement to perform some type of (unclearly defined) “selecting” and the subsequent “administering”, while others – particularly in view of the preamble language “determining if a subject…is likely to have therapeutic benefit…”, as well as the lack of clarity with regard to what “based on a fold changer higher than 1.3” means – would reasonably interpret the claims as requiring nothing more than determination of expression levels in the recited sample types. Accordingly, further clarification is required.
Claim 36 is indefinite over the recitation of the limitation “the immune checkpoint blockage therapy” because claim 30 as amended employs this term in multiple different ways, and it is not clear what is being referenced via the use in claim 36 of the limitation “the immune checkpoint blockage therapy”. More particularly, claim 30 recites “an immune checkpoint blockade therapy targeting PD-1/PD-L1” at line 3, and subsequently recites “an immune checkpoint blockade therapy” (without the qualification “targeting PD-1/PD-l1”) at line 9. Clarification is therefore required with regard to what element(s) of the method of amended claim 30 are being further limited by claim 36.
New dependent claim 37 is indefinite over the recitation of the limitation “wherein the fold change is determined by dividing, for each gene in the set of genes, a transcript intensity in the tumor sample with a transcript intensity in the normal histologically matched sample”. While it is noted that this language does clarify that “fold change” (in claim 37) refers to tumor sample transcript intensity divided by normal sample transcript intensity, independent claim 30 employs a “fold change higher than 1.3” for the set of genes as a criterion, and the language of claim 37 does not make clear how the values for each gene (calculated as specified in claim 37) relate to the “fold change” of the set of claim 30. As a “fold change higher than 1.3” is a critical (albeit unclear) limitation of independent claim 30, further clarification of both claims (including claim 37 with regard to how the individual values of claim 37 relate to the “set” value of claim 30) is needed to ensure that one of ordinary skill in the art is reasonably apprised of the boundaries of the claims.
Claim Rejections - 35 USC § 103
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claim(s) 30, 36, and 37 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Szeto (US 2022/0290250 A1 [published 15 Sept 2022; effective filing date 22 Aug 2019]; previously cited) in view of Zhang et al (Arch Gynecol Obstet 295:705-712 [2017]; previously cited).
It is again noted that the portions of the Szeto reference relied upon herein are also described in US provisional application 62/890,464, filed 22 August 2019. Additionally, the claims remain indefinite for the reasons given above; all that is clearly required by the claims as presently written is a method in which “the expression level of a set of genes comprising or consisting of PD-L2, CTLA-4, LAG3, TLR4 and FOXP3 is determined in a tumor sample and a normal histologically matched sample from the patient”, as the manner and type of conclusions to be drawn based upon those expression levels is unclear (and further, the preamble recites a method “for determining if” a subject is susceptible, such that no particular outcome is required by these claims). With regard to the newly recited activities of “selecting a patient” and ‘administering a therapeutic agent”, as discussed above these activities may reasonably be interpreted as optional/contingent on a possible (but not required) outcome of the (unclearly defined) “fold change” of the expression of the recited set of genes.
Szeto disclose that there is a need in the art to identify “which patients are likely to benefit from” treatments including PD-1/PD-L1 inhibitors (see, e.g., paragraphs 5-10). To address this need, Szeto teach methods of identifying tumor patients for treatment with particular therapies “based on differential checkpoint expression patterns”, with particular methods comprising obtaining expression data from “a tumor cell and matched normal cell” for genes of a group including CTLA4, LAG3, PDL2, and FOXP3 (see entire reference, particularly, e.g., paragraphs 12-17). Given the lack of clarity of the claim language discussed above, Szeto et al thus meet all requirements of the claims, other than the inclusion of TLR4 in gene expression testing. It is noted that the types of cancer taught by Szeto include cervical cancer; see paragraph 15.
Zhang et al teach that both FOXP3 (one of the genes taught by Szeto) and TLR4 were found to exhibit elevated expression in cervical cancer cells as compared to heathy control samples, and conclude that their results “demonstrate that the expression of both Foxp3 and TLR4 was closely related to malignant biological behaviors of tumors” (see entire reference, particularly the Abstract; page 706, left column; Results at pages 707-708). Zhang et al further state that their finding indicate a possible role for FoxP3 and TLR4 in immune escape, suggesting that they may be new targets for the “immunological treatment of cervical cancer” (i.e., for therapies of the type discussed by Szeto).
In view of the teachings of Zhang et al, it would have been prima facie obvious before the effective filing date of the claimed invention to have modified the methods of Szeto so as to have included the TLR4 gene in the group of genes tested by Szeto (particularly when evaluating gene expression in cervical cancer as compared to matched normal cervical samples). As Zhang et al demonstrate that both FOXP3 and TLR4 exhibit altered expression in association with “malignant biological behavior of tumors”, and suggest considering expression both of these genes with regard to identifying tumors that may be targeted by immunotherapies, an ordinary artisan would have been motivated to have made such a modification simply for the benefit of gathering additional expression data relevant to tumor status that might aid in selecting an appropriate treatment/therapy (as again, the claims as written require nothing more than gathering and comparing expression data regarding the recited multiple samples). Additionally, given the detailed guidance provided by Szeto (as well as Zhang et al), an ordinary artisan would have had a reasonable expectation of success in so modifying the method of Szeto.
With further regard to dependent claim 36, while it is noted that the cited art does suggest providing an appropriate therapy (including an anti-PD-1 or anti-PD-L1 antibody) to a patient based on gene expression patterns indicative of a likelihood of response thereto, as the type of subject referenced in these claims is not in fact required (given the language of independent claim 30), this claim is obvious for the same reasons given above regarding claim 30. More particularly, the “administering” of claims 36 is a conditional/contingent activity that is performed with regard to a subject “likely to have therapeutic benefit”, but claim 30 does not require that such a subject be “determined”. “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met” (MPEP 2111.04(II)).
With further regard to new claim 37, this claim is indefinite as discussed above, and the language of the claim simply recites how “the fold change is determined” (although it is reiterated that the manner in which claim 30 is further limited is unclear). The claim as written sets forth no further active/manipulative steps, but appears to encompass simply thinking about/performing calculations related to the results of an active/wet method step (the gathered gene expression data). Such an activity is simply an instructional limitation added to a method suggested by the prior art, i.e., nonfunctional descriptive material that need not be given patentable weight when comparing the claimed invention to the prior art (see MPEP 2111.05). Accordingly, the method of claim 37 is also obvious for the reasons set forth above.
The Reply of 07 May 2026 traverses the prior rejection of claims under 35 USC 103 on the following grounds. Applicant summarizes requirements of an obviousness rejection and argues that “the combined references fail to teach all elements of the claims” (Reply page 11). Applicant argues that “the combined references do not disclose any likelihood of therapeutic benefit for treatment with immune checkpoint blockade therapy based on expression levels of the claimed set of genes….the likelihood of success being inversely correlated to the fold change of the expression of the set of genes”, and further that Szeto teaches that “therapy is recommended when CTLA-4, LAG3, and FoxP3 are overexpressed” in a tumor cell sample, asserting that this teaches away from what is claimed (Reply page 11). Applicant further argues that a skilled artisan “would not have been motivated to combine Zhang with Szeto and modify Szeto ‘simply for the benefit of gathering additional expression data relevant to tumor status that might aid in selecting an appropriate treatment/therapy’”, as Szeto “specifically taught the use of the discovered association of certain gene mutations with differential expression of certain checkpoint inhibitors” and there is “no associated mutation” known for TLR4, such that this modification “would not have aided Szeto’s method” (Reply page 12).
These arguments have been thoroughly considered but are not persuasive.
With regard to Applicant’s arguments that the prior art fails to teach or suggest a fold change required by the claims, and that Szeto teaches away from the claimed invention, it is noted that: a) as discussed above, the claim language “wherein….the likelihood of therapeutic benefit of a treatment…is inversely correlated with the fold change of the expression for the set of genes” is unclear/indefinite; b) even if such “wherein” language were clear with regard to a defined type of “fold change”, such language constitutes a statement of what is indicated by a possible but not required outcome regarding expression levels testing and comparison rather than a recitation of a further required concrete limitation (e.g., a requirement for a particular structure, or that steps be performed, etc.), such that claim scope is not limited by this language (MPEP 2111.04); and c) given that there is no clearly recited concrete requirement for any particular type of “fold change”, Szeto cannot reasonably be said to “teach away” from what is claimed. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Regarding Applicant’s arguments that there is no motivation to combine Zhang with Szeto, it is noted that a reference “may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see MPEP 2123, citing to Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)), and that a rationale for modifying a reference provided in a rejection under 35 USC 103 need not rely on the same result, purpose, or advantage discovered by the inventor (see MPEP 2144(IV)). In the present case, the teachings of the prior art are sufficient to suggest all clearly recited limitations of the claimed invention (as discussed in the rejection itself). It is reiterated that Zhang teaches both FoxP3 (overlapping with the gene group taught by Szeto) and TLR4, and state that their findings indicate a possible role for FoxP3 and TLR4 in immune escape, suggesting that these may be new targets for the “immunological treatment of cervical cancer”. Thus when the teachings of both references as a whole are considered, an ordinary artisan would have recognized a benefit in modifying Szeto in view of Zhang, resulting in a method meeting all clearly recited requirements of the present claims (which is what the references must suggest to support a rejection under 35 USC 103).
Claim Rejections - 35 USC § 101
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 30, 36, and 37 remain/are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Independent claim 30 as amended is drawn to a method “for determining if a subject suffering from a cancer is likely to have a therapeutic benefit from treatment with an immune checkpoint blockade therapy targeting PD-1/PD-L1 wherein the expression level of a set of genes comprising or consisting of PD-L2, CTLA-4, LAG3, TLR4 and FOXP3 is determined in a tumor sample and normal histologically matched sample from the patient and the likelihood of a therapeutic benefit of a treatment with the immune checkpoint blockade therapy targeting PD-1/PD-L1 is inversely correlated with the fold change of the expression for the set of genes, wherein the method comprises selecting a patient likely to have a therapeutic benefit of a treatment with an immune checkpoint blockade therapy based on a fold change higher than 1.3, and administering a therapeutic amount of the immune checkpoint blockade therapy to the selected patient”.
It is again noted that (as discussed above) the language of claim 30 is indefinite for multiple reasons, and that at least one reasonable interpretation of the claim does not require the newly added “selecting” and “administering”, as such a requirement is not made clear by the present claim language. The recited limitations of “determining” if a subject is “likely to have” a benefit and “expression level of a set of genes….is determined” for two types of samples “and the likelihood….is inversely correlated…” encompass simply thinking about test results “determined” with respect to samples from a patient and thinking about/drawing conclusions about what those test results mean, i.e., activities that may be conducted entirely in the human mind, a type of abstract idea. This judicial exception is not integrated into a practical application because nothing beyond the recited abstract idea is clearly required by the present claim language. The claim encompasses, e.g., acquiring and analyzing previously obtained data, as well as data gathering practiced with regard to samples tested with regard to expression levels; the former embodiments require nothing more than thought, while the later embodiments encompass data gathering steps that do not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because even to the extent that the claims may require some type of active/manipulative testing of samples (which they presently do not), activities of “determining” expression levels of the type set forth in the claim were well-understood, routine, and conventional before Applicant’s effective filing date; see, e.g., Szeto (US 2022/0290250 A1) and Zhang et al (Arch Gynecol Obstet 295:705-712 [2017]), which are cited and discussed above. It is also noted that while the claims do not currently require a physical/active testing of expression levels of the recited gene grouping, even if they did, the altered expression of a particular group of genes as it naturally occurs in the context of cancer would not amount to “more” than a JE, as such expression levels themselves are a natural phenomenon (i.e., a further type of JE, rather than something “more” than a JE).
With further regard to claim 36, this claim does not require a practical application of a JE, or anything “significantly more” than a JE, as the activity recited pertains to “immune checkpoint blockade therapy”, and it is unclear how amended claim 30 is being further limited (see the rejection under 35 USC 112(b) above). Further, to the extent that the claim may further limit the “subject…likely to have therapeutic benefit” with such therapy, and/or the type of therapy referenced in the ”selecting” and “administering” of amended claim 30, neither of these claim limitations are required features of what is being claimed. Thus, claim 36 does not add anything amount to either a practical application or something “significantly more” than a JE. Regarding new dependent claim 37, this claim, which is indefinite for the reasons indicated above, simply recites a further calculation via which “fold change is determined”, which is an additional abstract idea, rather than an application of a JE, or something more than a JE. An inventive concept cannot be furnished by a judicial exception (i.e., a law of nature/natural phenomenon/abstract idea) itself (see MPEP 2106.05(I)).
Thus, none of claims 30, 36, and 37 is directed to patent eligible subject matter.
The Reply of 07 May 2026 traverses the prior rejection of claims under 35 USC 101 on the following grounds. Applicant argues that independent claim 30 as amended recites “that the method further comprises selecting a patient susceptible to have a therapeutic benefit of a treatment with an immune checkpoint blockade therapy based on a fold change higher than 1.3 and administering a therapeutic amount of the immune checkpoint blockade therapy to t he selected patient”, urging that the claims as amended are thus “directed to particular methods of treatment” that are patient eligible (Reply pages 12-13). Applicant states that “the claims recite more than a relationship between gene expression and a susceptibility to a therapy; they recite a method of treating patient based on an inverse relationship between expression of a certain set of genes and a therapeutic benefit from an immune checkpoint blockage therapy that makes immune checkpoint blockade therapy safer by lowering the risk of toxic effects on patients that are not likely to have therapeutic benefit…”, and thus argues that “the claims are not directed to an abstract idea” (Reply page 13). These arguments have been thoroughly considered but are not persuasive because the limitations relied upon in Applicant’s arguments are not clearly present in the claims. More particularly, it is not clear that the claims do in fact require any treating/administering (as again there are multiple reasonable interpretations of Applicant’s claim language), and thus there is not an actual requirement for a “particular treatment” providing the benefit(s) upon which Applicant’s arguments rely. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
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.
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
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