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 .
Claim Status/Action Summary
This action is in response to the papers filed on February 6, 2025.
Claim 18 was canceled in the response. Claims 16-17 and 19-24 are under examination. No other claims are currently pending in the application.
Any objections and rejections not reiterated below are hereby withdrawn.
The objections of record to the specification are withdrawn in view of the amendments to the specification.
The objections of record to the drawings are withdrawn in view of the replacement drawings filed with the response.
The rejections of record under 35 U.S.C. 112(b) have been withdrawn in view of the amendments to the claims. A new rejection necessitated by these amendments under this statute has been added.
The 102 rejection of record over Heo et al. has been withdrawn.
Priority/Effective Filing Date
The present application, filed on June 29, 2023, is a 371 of PCR/KR2022/002687, filed on February 24, 2022, and claims foreign priority to REPUBLIC OF KOREA 10-2021-0055047, filed on April 28, 2021. It is noted that no English language translations of the foreign priority documents have been provided.
Drawings
The drawings filed on February 6, 2026 are acceptable.
Claim Rejections - 35 USC § 112(b)
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.
Claims 16-17 and 19-24 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
This is a new grounds of rejection necessitated by the amendments to the claims.
Regarding claim 16, the claim phrase: “the cancer includes gastric cancer, colorectal cancer, biliary tract cancer, lung cancer, skin cancer, head and neck cancer, Hodgkin’s lymphoma, kidney cancer, and urothelial cell carcinoma” renders the claim indefinite because it appears to require that the cancer includes (i.e. comprises) the combination of all of the recited cancers. It is unclear how “the cancer” as recited by the claim is intended to comprise all of these different subtypes of cancers characterized by different primary location of origin (e.g. colorectal cancer) and tissue type of origin (e.g. urothelial cell carcinoma).
Claims 17 and 19-24 are rejected as indefinite because they depend from, and thus include the indefinite limitations of, claim 16.
Claim Interpretation
Claim 1, as amended, recites “a method for predicting responsiveness of a cancer to an anticancer agent, comprising: measuring the level of genes including [ARMCX1, PRKD1, and TYK2]”… “wherein the anticancer agent is one or more selected from the group consisting of: atezolizumab, avelumab, and durvalumab, wherein the cancer includes: gastric cancer, colorectal cancer, Hodgkin’s lymphoma, kidney cancer, and urothelial carcinoma, and wherein the subject is a human patient.”
The claim recites a combination of genes including ARMCX1, PRKD1, and TYK2.
The claim recites an anticancer agent that is one or more agent selected from a closed group (“consisting of” alternative PD-L1 inhibitors).
The claim recites “the cancer includes” a list of alternative cancers recited as a combination (i.e. gastric cancer… and urothelial carcinoma).
The open “comprising” and “including” claim language has been interpreted in the following ways for the amended claim 1:
The combination of genes includes at least the combination of the three positively recited genes (i.e. comprises the combination), but is not limited to measuring only the three recited genes.
The list of PD-L1 inhibitors is interpreted as a closed set of alternatives (i.e. a Markush group)
The list of cancers “including” “gastric cancer, colorectal cancer, biliary tract cancer, lung cancer, skin cancer, head and neck cancer, Hodgkin’s lymphoma, kidney cancer, and urothelial cell carcinoma”, as best understood, is being interpreted as an open list of alternative cancers for the purposes of the rejections which follow.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
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.
Claims 16-17 and 19-24 are/remain rejected under 35 U.S.C. 112(a) because the specification, while being enabling for predicting responsiveness of gastric cancer to (pembrolizumab, atezolizumab, avelumab, or durvalumab) (i.e. anti-PD1/PD-L1 antibodies) by a method comprising measuring genes including ARMCX1, PRKD1, TYK2, and UCHL1 expression levels and a PD-L1 combined positive score (i.e. the “IMAGiC” score), does not reasonably provide enablement for predicting responsiveness to the recited anticancer agents in any/all biological samples derived from any human subject having any cancer. 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 and/or use the invention commensurate in scope with these claims.
This rejection has been updated as necessitated by the amendments to the claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of U.S.C. 112(a) have been described by the court in In re Wands, 8 USPQ2d 1400 (CAFC 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 guidance or direction 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.”
The nature and breadth of the claims
Claims 16-17 and 19-24 are drawn to methods for predicting responsiveness to anti-PD-L1 antibodies atezolizumab, avelumab or durvalumab comprising active process steps comprising measuring the expression level of genes including: ARMCX1, PRKD1, and TYK2 (claim 16) or additionally UCHL1 (claim 17). The claims encompass measuring said expression level(s) in any biological sample (i.e. any tissue, any exudate, fluid, etc.) from any human patient (claim 16). Claims 23 and 24 further limit the “biological sample” to “a cancer patient-derived tissue” (i.e. any tissue collected from any patient with cancer), and further to “a paraffin-embedded tissue”, respectively.
As broadly claimed, the “cancer includ[ing] (i.e. comprising) gastric cancer, colorectal cancer, biliary tract cancer, lung cancer, skin cancer, head and neck cancer, Hodgkin’s lymphoma, kidney cancer, and urothelial cell carcinoma”, “cancer patient-derived tissue” or “cancer patient-derived, paraffin-embedded tissue”, recited by claims 23 and 24, are not limited to any particular type of cancer because the claim language in the independent claim 16 is open (“comprising…wherein the cancer includes…”) and may be interpreted as encompassing any cancer.
The unpredictability of the art and the state of the prior art
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The art teaches that cancers are classified in two ways: by the type of tissue in which the cancer originates (i.e. based on histological type, such as “epithelial tissues” also referred to as “carcinomas” ) and by primary site (i.e. where in the body the cancer first developed, for example “gastric cancer”). SEER Training Modules, Cancer Classification. U.S. National Institutes of Health, National Cancer Institute. July 2, 2025. Regarding classification by primary site, the art teaches that primary site classification is not as accurate regarding any particular quality of the tumor beyond where a particular tumor is located in the body SEER Training Modules, Cancer Types by Site. U.S. National Institutes of Health, National Cancer Institute. July 2, 2025.
Applicant’s own near-filing date publication, Kim et al., “Validation of the Combined Biomarker for Prediction of Response to Checkpoint Inhibitor in Patients with Advanced Cancer” Cancers 2021, 13, 2316 (published May 12, 2021), teaches limitations to the broad applicability of the combination of all of the recited gene expression markers and PD-L1 expression level to different cancer types.
Quoting from Kim et al., 2021:
“In the current study, we built a model [“IMAGiC”] with the composition of four genes [ARMCX1, PRKD1, TYK2, and UCHL1] selected through the differentially expressed gene analysis and PD-L1 CPS… “Given that IMAGiC platform correlates well with high TMB in various tumor types and predicted response to checkpoint inhibitor in patients with high-MSI tumor and not responding to immunotherapy, the predictive function of the IMAGiC is thought to be at least equal or superior to PD-L1 expression. Although the superb performance of IMAGiC was not proven in the present study, possibly due to a small number of cases, it could be considered that the IMAGiC is one of the multifactorial synergistic biomarkers, and we are planning to perform a prospective clinical trial to prove this in a larger cohort.
This study has some inherent limitations. First, as we tried to construct a simplified predictive biomarker by analyzing multiple genomically heterogeneous tumors at once, it might be difficult to generalize the results due to differences in the characteristics of each cancer type. Second, the statistically determined cutoff point for the IMAGiC score in the current study would need to be validated in a generalized and larger dataset. Third, a relatively short follow-up period prevented the maturation of survival data (PFS and OS). Nevertheless, despite these drawbacks, our dichotomized IMAGiC score was identified as a robust biomarker for better predicting treatment response and improved PFS in patients treated with checkpoint blockade treatment.” (Kim et al., page 10).
To summarize, Applicant’s near-filing date publication teaches a biomarker “IMAGiC” comprising expression levels of all of the recited genes and the drug target PD-L1 correlates well with other measures of responsiveness to therapy, but the presented data is hampered by small sample sizes, heterogenous cancer types, insufficient follow-up period, lack of statistical support for a cutoff value, and “is thought to be at least equal or superior to PD-L1 expression” (i.e. the IMAGiC biomarker comprising measuring PD-L1 expression does not demonstrably improve over measuring PD-L1 expression alone).
Applicant’s own prior art publication Heo et al., “Combined biomarker for prediction of response to an immune checkpoint inhibitor in metastatic gastric cancer” Precision and Future Medicine (2019) teaches methods comprising combining PD-L1 CPS (i.e. expression) and measuring differential gene expression between gastric cancer patients who had responded to pembrolizumab (an anti-PD-1 anticancer agent) and those who did not respond. Heo et al. further teach TYK2, PRKD1, ARMCX1, and UCHL1 are differentially expressed in gastric cancer. Heo et al. finally teach validating the association between response to an immune checkpoint inhibitor (ICI) drug (pembrolizumab, a PD-1 inhibitor) and gene expression using publicly available datasets as a distinct validation cohort.
Guidance in the specification and working examples
The specification provides similar data to that provided by Kim et al., 2021, wherein gene expression of the combination of all of the recited genes and PD-L1 are measured and correlated to observed ICI drug responses for 73 patients having diverse cancers (table 1).
The specification does not teach validation of any combination of recited genes “in a larger dataset” as described by Kim et al. (see above), or any guidance as to how to determine what expression level(s) are predictive of response to the recited drugs (i.e. absolute values, relative values compared to a control or reference) or how to ascertain a statistically valid cutoff therefore.
Quantity of experimentation
The quantity of experimentation in this area is extremely large since there are a number of parameters which would have to be studied to use the invention for any cancer in a human. As described by Kim et al., the combined biomarker comprising expression levels of PD-L1 and all of ARMCX1, PRKD1, TYK2, and UCHL1 (i.e. “IMAGiC”) requires further study in large cohorts with statistically meaningful numbers of patients having the recited cancer types with longer follow-up times to allow for collection of data necessary to classify patients based on survival data (Kim et al., page 10 (and quoted above)).
Together, the specification and the art teach that “cancer” is a very broad and diverse category comprising hundreds of different species (according to the two classification schemes described above). Furthermore, the specification and the art teach there are many unpredictable variables comprising at least: intra-tumoral heterogeneity (i.e. a tumor sample may not be a fully representative sample of the drug-sensitivity for an entire tumor), the need for validation at each specific disease site (i.e. gastric, colorectal, biliary tract, lung, etc.), the need for selection of a set of genes for each tumor subtype (i.e. gastric, colorectal, biliary tract, lung, all carcinomas, etc.), and the lack of pre-existing suitable datasets (i.e. comprising pre-treatment gene expression data and subsequent response to anti-PD-L1 drugs for statistically relevant numbers of patients having each type of cancer of interest) from which suitable markers can be discovered and against which predictive models can be validated.
This would require significant inventive effort including generating large clinical trials spanning the genera “subject” (i.e. all animals, all tissue types, etc.) and “patient with cancer” (i.e. all cancer types) with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the successive steps.
Level of skill in the art
The level of skill in the art is deemed to be high.
Conclusion
In the instant case, given the extremely broad claims in a highly unpredictable art, the large quantity of experimentation required to define and resolve these unpredictable variables, the lack of guidance provided in the specification and art, and lack of working examples, balanced only against the high level of skill in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claims as broadly written.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 16-17, 19-20 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Heo et al., “Combined biomarker for prediction of response to an immune checkpoint inhibitor in metastatic gastric cancer” Precision and Future Medicine (2019) in view of Liang et al., “Compare the efficacy and safety of programmed cell death-1 (PD1) and programmed cell death ligand-1 (PD-L1) inhibitors for advanced nonsmall cell lung cancer: a Bayesian analysis”. Translational Lung Cancer Research 2020;9(4):1302-13323.
This rejection has been updated as necessitated by the amendments to the claims.
This rejection is made over the enabled scope of the claims described in the 112(a) rejection above.
Regarding claim 16, Heo et al. teaches a method of predicting responsiveness to pembrolizumab (a PD-L1 binding antibody that is an immune checkpoint inhibitor) comprising measuring the gene expression levels of ARMCX1, PRKD1, and TYK2 (Heo et al., Figure 1, red arrows added) in biological samples from subjects with gastric cancer.
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Liang et al. teaches various clinical considerations for treating lung cancer patients with alternative immune checkpoint inhibitors comprising pembrolizumab, atezolizumab, durvalumab, and avelumab) (Liang et al., abstract). Liang et al. teach that pembrolizumab is preferred for patients with high PD-L1 expression in first line settings, while durvalumab had the greatest effect in tumor shrinkage, and atezolizumab was the safest in terms of adverse events. (Liang et al., abstract).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by Heo et al. for predicting responsiveness to the PD-1/PD-L1 inhibitor pembrolizumab comprising measuring expression of ARMCX1, PRKD1, TYK2, and UCHL1 to similarly predict responsiveness to the art-recognized alternative PD-1/PD-L1 inhibitors atezolizumab, avelumab, and durvalumab for treatment of lung cancer.
The ordinary artisan would have been motivated to modify the teachings of Heo et al. with the teachings of Liang et al. because Liang et al. teaches that the different PD-1/PD-L1 inhibitors act on the same molecular targets/basis (Liang et al., page 1303, column 1) and are preferred for specific applications based on patient characteristics/clinical history (i.e. previous treatment, adverse events, general health, etc.) (Liang et al., page 1320, column 1).
Regarding claim 17, Heo et al. further teach measuring the expression level of UCHL1 (Heo et al., Figure 1).
Regarding claims 19 and 20, Heo et al. teach measuring mRNA expression levels of the recited genes by NanoString analysis (i.e. a direct digital detection system) (Heo et al., page 3, column 1, paragraph 3).
Regarding claim 23, Heo et al. teach the biological sample is a cancer patient-derived tissue (Heo et al., abstract).
Regarding claim 24, Heo et al. teach the biological sample is paraffin-embedded tissue (Heo et al., abstract).
Response to arguments
The response asserts that (a) there is no motivation to modify and (b) there is no reasonable expectation of success.
The response asserts that motivation is lacking because: Heo et al. teach a predictive model (comprising the same genes as presently claimed) for response to a PD-1 inhibitor (Pembrolizumab) while the present claims require that the anticancer agent is selected from a group of PD-L1 inhibitors, (a of a lack of “head to head comparisons and need for additional validation when comparing PD-1 and PD-L1 inhibitors” and “PD-1 inhibitors and PD-L1 inhibitors have different molecular targets and act at different points in the immune checkpoint pathway”.
These assertions have been thoroughly reviewed and are not persuasive. As described above, the ordinary artisan would have been well-informed that PD-1 inhibitors (such as pembrolizumab) and PD-L1 inhibitors (such as atezolizumab, avelumab, and durvalumab), collectively belonging to the group of antibody drugs known as “immune checkpoint blockade (ICB)” or “immune checkpoint inhibitor (ICI)” drugs. The anti-PD-1/PD-L1 all act through a common mechanism wherein the antibody drug binds to either PD-1 (a receptor) or PD-L1 (the ligand of PD-1), blocking the interaction between the two target molecules (Liang et al., introduction, paragraph 1 ; Heo et al., Discussion paragraph 2). Furthermore, PD-1 (pembrolizumab) and PD-L1 inhibitors (atezolizumab) are both approved to treat the same cancer(s) (lung cancer) (Liang et al., page 1317, column 1, paragraph 2). Therefore, the ordinary artisan would have recognized that PD-1 and PD-L1 inhibitors: are effective against the same cancers, act at the same step in the PD-1/PD-L1 molecular pathway, and both target the interaction between PD-1 and PD-L1.
The response asserts “there is no indication in the cited reference that a predictive model based on PD-1 inhibitors would be applicable to PD-L1 inhibitors”.
This assertion has been thoroughly reviewed and is not persuasive. As described above, Heo et al. identify genes that are differentially expressed between patients who responded to PD-1 inhibitor therapy (pembrolizumab) and those who did not respond to the treatment (including all of the recited genes in the present claims). Heo et al. and Liang et al. teach PD-1 and PD-L1 act by binding either member of the interaction pair PD-1 and PD-L1 such that PD-1 is unable to bind its ligand PD-1 (either because the receptor site on PD-1 is blocked by the antibody (e.g. pembrolizumab) or because the receptor-binding site on the ligand PD-L1 is blocked by the antibody (e.g. atezolizumab, avelumab, durvalumab, etc.).
The ordinary artisan would therefore have had a reasonable expectation that genes that are differentially regulated by an anti-PD-1 drug (pembrolizumab), which acts by preventing the interaction between PD-1 and its ligand PD-L1, would also be differentially regulated by an anti-PD-L1 drug (e.g. atezolizumab), which acts by preventing the interaction between PD-1 and its ligand PD-L1 (i.e. “signatures” of responsiveness to PD-1 and PD-L1 inhibitors would be expected to be the same).
Claims 21-22 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Heo et al. in view of Liang et al as applied to claims 16-20 and 23-24 above, and further in view of Silva et al., “Quantifying gene expression: the importance of being subtle”. Molecular Systems Biology 12:885 (2016).
Regarding claims 21 and 22, Heo et al. in view of Liang et al. do not teach measuring gene expression of the recited genes by measuring proteins encoded by the genes.
However, Silva et al. teach gene expression is regulated at multiple levels (i.e. transcription, RNA stability, translation, post-translational stability) and while the bulk of variance in gene expression for many genes can be predicted by its mRNA concentration, many genes’ protein concentration can vary by up to two orders of magnitude in different tissue types with similar mRNA concentrations. Similarly, many genes’ mRNA concentrations can vary by up to tenfold at similar protein concentrations. (Silva et al., page 2, column 1).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by Heo et al. comprising measuring mRNA levels of each of the recited genes by measuring protein levels of each of the recited genes because of the teaching of Silva et al. that expression levels of protein-coding genes are regulated pre- and post- translationally, and for many genes, measurement of mRNA levels only does not accurately reflect “gene expression” in all tissue types. Therefore, the ordinary artisan would have been motivated to measure protein levels for the recited genes by any conventional method, such as western blot, using primary antibodies commercially available prior to the effective filing date of the claimed invention.
Response to arguments
The response asserts “Silva fails to remedy the deficiencies of Heo and Liang”. This assertion has been reviewed and is not persuasive for the reasons described above.
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.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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